An important parameter in the development of a new drug is the drug's affinity to the identified target (protein/enzyme). Predicting the ligand binding to the target (protein/enzyme) by molecular simulation would allow the synthesis to be restricted to the most promising compounds.A restricted hybrid HF-DFT calculation was performed in order to obtain the most stable conformer of each ligand and a series of DFT calculations using the B3LYP levels with 6-31G* basis set has been conducted. The docking studies of the quinolone compounds will be performed with the CLC Drug Discovery Workbench to identify and visualize the ligand-receptor interaction mode.

Natural products from plants such as, chemopreventive agents attract huge attention because of their low toxicity and high specificity. The rational drug design in combination with structure based modeling and rapid screening methods offer significant potential for identifying and developing lead anticancer molecules. Thus, the molecular docking method plays an important role in screening a large set of molecules based on their free binding energies and proposes structural hypotheses of how the molecules can inhibit the target. Several peptide based therapeutics have been developed to combat several health disorders including cancers, metabolic disorders, heart-related, and infectious diseases. Despite the discovery of hundreds of such therapeutic peptides however, only few peptide-based drugs have made it to the market. Moreover, until date the activities of cyclic peptides towards molecular targets such as protein kinases, proteases, and apoptosis related proteins have never been explored. In this study we explore the in silico kinase and protease inhibitor potentials of cyclosaplin as well as study the interactions of cyclosaplin with other cancer-related proteins. Previously, the structure of cyclosaplin was elucidated by molecular modeling associated with dynamics that was used in the current study. Docking studies showed strong affinity of cyclosaplin towards cancer-related proteins. The binding affinity closer to 10 indicated efficient binding. Cyclosaplin showed strong binding affinities towards protein kinases such as EGFR, VEGFR2, PKB and p38 indicating its potential role in protein kinase inhibition. Moreover, it displayed strong binding affinity to apoptosis related proteins and revealed the possible role of cyclosaplin in apoptotic cell death. The protein-ligand interactions using LigPlot displayed some similar interactions between cyclosaplin and peptide-based ligands especially in case of protein kinases and a few apoptosis related proteins. Thus, the in silico analyses gave an insight of cyclosaplin as a potential apoptosis inducer and protein kinase inhibitor.

The novel coronavirus disease 19 (COVID-19) has resulted in an estimated 20 million excess deaths and the recent resurgence of COVID-19 in China is predicted to result in up to 1 million deaths over the next few months. With vaccines unable to halt transmission it is important to continue our quest for safe, effective, affordable drugs that will be available to all countries. Drug repurposing is one of the strategies being explored in this context. Recently, out of 7,817 approved drugs, 214 candidates were systematically down-selected using a combination of 11 filters including approval status, assay data against SARS-CoV-2, pharmacokinetic, pharmacodynamic and toxicity profiles. These drugs were subjected in this study to virtual screening against various targets of SARS-CoV-2 followed by molecular dynamic studies of the best scoring ligands against each target. The chosen molecular targets were Spike receptor binding domain, Nucleocapsid protein RNA binding domain, and key non-structural proteins 3, 5, 12, 13 and 14. Four drugs approved for other indications — alendronate, cromolyn, natamycin and treprostinil — look sufficiently promising from our in silicostudies to warrant further in vitro and in vivo investigations as appropriate to ascertain their extent of anti-viral activities.

The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral Integrase (IN) enzyme catalyses integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG) and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of Integrase Strand Transfer Inhibitors (INSTIs). In this study, we applied computational methods of molecular modelling and docking to analyse the effect of NOPs on the full-length IN structure and INSTI binding. We identified 16 NOPs within the Cameroonian derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any effect on INSTI binding. INSTIs displayed similar binding affinities to each IN structure. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment naïve populations. This study supports the use of second-generation INSTI DTG as part of first-line combination antiretroviral therapy (cART) regimens, due to DTG possessing a stronger genetic barrier to the emergence of drug resistance.

Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative and antineoplastic activities. Recently, different studies have shown that flavonoid have the potential to inhibit BET bromodomains. Previous reports suggest that flavonoids are putative inhibitors of the ZA channel due to their orientation and interactions with P86, V87, L92, L94 and N140. Herein, a comprehensive characterization of the binding mode of the biflavonoid amentoflavone and fisetin is discussed. To this end, both compounds were docked with BRD4 using four docking programs. Results were post-processed with protein-ligand interaction fingerprints. To gain further insights into the binding mode of the two natural products, docking results were further analyzed with molecular dynamics. Results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as basis for scaffold optimization and further characterization of flavonoids as BET inhibitors.

The global pandemic caused by the new SARS-COV-2 coronavirus makes it necessary to search for drugs for its control. Within of this research it has been known that the ivermectin drug, a FDA-approved drugs which is formulated as an 80:20 mixture of ivermectin B1a and B1b and used commonly for parasitic infections, has an inhibitory effect on viruses, includes SARS-COV-2 at in vitro level. In the particular case of SARS-COV-2 its mechanism of action remains elusive and controversial. Interestingly, the energy of interaction of ivermectin with any of the proteins the SARS-CoV-2 and the possible structural alterations at the protein level that this drug can cause have not been reported. In this sense, we carried out a bioinformatics study with docking strategies and molecular dynamics to predict the binding and disturbance induced by ivermectin in proteins associated with SARS-CoV-2. We use DockThor and Molegro docking scores. The DockThor server and myPresto software were used to build complexes and dynamics studies, respectively. The results obtained suggested that ivermectin is capable of docking with the 3CL protease and the HR2 domain, and may promote structural changes in these proteins by inducing unfolding/folding. Specifically, ivermectin brings protease to a significantly more deployed conformational state and the HR2 domain to a more compact state compared to the native state. Finally, it is shown that B1a and B1b macrocyclic lactones have a behavior different from to each target protein. These results suggest a possible inhibitory effect against SARS-CoV-2 due to a synergistic role of this drug to spontaneously bind to two important proteins involve in the proliferation of this virus. However, more studies are required on this possible mechanism of action.

Histone Lysine Specific Demethylase 1 (LSD1) is overexpressed in many cancers and become a new target for anticancer drugs. In recent years, the small molecule inhibitors with various structures targeting LSD1 have been reported. Here we report the binding interaction modes of a series of thieno[3,2-b]pyrrole-5-carboxamides LSD1 inhibitors using molecular docking, three dimensional quantitative structure-activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA q²=0.783, r²=0.944, r²_pred=0.851) and Comparative molecular similarity indices analysis (CoMSIA q²=0.728, r²=0.982, r²_pred=0.814) were used to establish 3D-QSAR models, which had good verification and prediction capabilities. Based on the contour maps and the information of molecular docking, 8 novel small molecules were designed in silico, among which compounds D4, D5 and D8 with high predictive activity were subjected to further molecular dynamics simulations (MD), and their possible binding modes were explored. It was found that Asn535 plays a crucial role in stabilizing the inhibitors. Furthermore, the ADME and bioavailability prediction for D4, D5 and D8 were carried out. The results would provide valuable guidance for designing new reversible LSD1 inhibitors in the future.

Prototype of a family of at least nine members, c-src tyrosine kinase is a therapeutically interesting target, because its inhibition might be of interest not only in a number of malignancies, but also in a diverse array of conditions, from neurodegenerative pathologies to certain viral infections. Computational methods in drug discovery are considerably cheaper than conventional methods and offer opportunities of screening very large numbers of compounds in conditions that would be simply impossible within the wet lab experimental settings. We have explored the use of global QSAR models and molecular ligand docking in the discovery of new c-src tyrosine kinase inhibitors. Using a data set of 1038 compounds from ChEMBL and 19 blocks of molecular descriptors, we have developed over 200 QSAR classification models, based on six machine learning algorithms and 17 feature selection methods. We have selected 49 with reasonably good performance (positive predictive value and balanced accuracy higher than 70% in nested cross validation) and the models were assembled by stacking with a simple majority vote and used for the virtual screening of over the “named” ZINC data set (over 100,000 compounds). 744 compounds were predicted by at least 50% of the QSAR models as active, 147 compounds were within the applicability domain and predicted by at least 75% of the models to be active. The latter 147 compounds were submitted to molecular ligand docking using Vina and Ledock, and a number of 90 were predicted to be active based on the binding energy. External data from CHEMBL and PUBCHEM confirmed that at least 7.83% (in the case of QSAR) or 6.67% (in the case of integrated QSAR and molecular docking) of the compounds are active on the c-src target.

Some α-Pyrone derivatives isolated from Alternaria phragmospora fungus showed promising anti leukemic activities, while others were inactive. CRM1/XPO1 (chromosome region maintenance 1 protein, also called exportin1 or PO1 in humans) has been chosen as a target for antileukemic molecular docking study for those compounds to understand their modes of interaction and structure activity relationships. The results showed that two (2 and 4), out of six, natural α-Pyrone derivatives exhibited well-established interactions with the amino acids of the receptor, which was in agreement with the experimental anti-leukemic results of these compounds. Moreover, twenty hypothetical chemically modified α-Pyrone derivatives (7-27) have been designed. Compounds 7, 8, 22 and 24 showed more efficient docking properties than the previously considered natural compounds.

We have synthesized quinoxaline analogs (1-25), characterized by 1HNMR and HREI-MS and evaluated for thymidine phosphorylase inhibition. Among the series, nineteen analogs showed better inhibition when compared with the standard inhibitor 7-Deazaxanthine (IC50 = 38.68 ± 4.42 µM). The most potent analog among the series is analog 25 with IC50 value 3.20 ± 0.10 µM. Sixteen analogs 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 21and 24 showed outstanding inhibition which is many folds better than the standard 7-Deazaxanthine. Two analogs 8 and 9 showed moderate inhibition. A structure- activity relationship has been established mainly based upon the substitution pattern on the phenyl ring. The binding interactions of the active compounds were confirmed through molecular docking studies.

Aurora kinase A (AURKA) is a normal cell proliferation-inducing enzyme encoded by AURKA gene, with over-expression observed in different types of malignancies. Hence, the goal is to find potential inhibitors against AURKA. In this study, molecular docking, Standard Precision and Extra Precision methods were employed. After the docking study, the ligands showed an extremely low binding score which suggested very high binding affinity of the ligands. Furthermore, Quantum polarized ligand docking (QPLD) was performed to predict the binding status of the molecules. Based on the binding affinity, the top four compounds were chosen for further analysis. The docked complexes were further analyzed in explicit water conditions using 100 ns molecular dynamics simulations and binding free energy calculation. Then, density functional theory (DFT) calculation was used to calculate the molecular properties of the molecules. Finally, systems biology experiments validated the molecular docking and molecular dynamics simulation studies and indicated that quercetin, kaempferol, luteolin and rutin could inhibit the AURKA. The results show that, these four molecules have high binding affinity to the AURKA and significant interactions (LEU139, GLU211and ALA213) were also identified with the hinge region of Aurora kinase A. Thus, LEU139, GLU211, and ALA213 were identified as the crucial protein mechanisms.

In the search of potent α-amylase inhibitors, we have synthesized seventeen derivatives of 2-mercaptobenzimidazole bearing sulfonamide (1-17) and evaluated for their α-amylase inhibitory potential. All compounds display a variable degree of α-amylase activity having IC50 values ranging between 0.90 ± 0.05 to 11.20 ± 0.30 µM when compared with the standard drug acarbose having IC50 value 1.70 ± 0.10 µM. Compound 1, 2, 11, 12 and 14 having IC50 values 1.40 ± 0.10, 1.30 ± 0.05, 0.90 ± 0.05, 1.60 ± 0.05 and 1.60 ± 0.10 µM respectively were found many folds better than the standard drug acarbose. The remaining analogs showed good inhibitory potentials. All the synthesized compounds were characterized by HREI-MS, 1H and 13C-NMR. Structure activity relationship (SAR) has been recognized for all newly synthesized analogs. Through molecular docking study, binding mode of active analogs with α-amylase enzyme was confirmed.

New class of triazinoindole bearing thiosemicarbazide (1-25) was synthesized and evaluated for α-glucosidase inhibitory potential. All synthesized analogues exhibited excellent inhibitory potential having IC50 values ranging from 1.30 ± 0.01 to 35.80 ± 0.80 µM when compared with the standard acarbose having IC50 value 38.60 ± 0.20 µM. Among series the analogues 1 and 23 was found the most potent having IC50 values 1.30 ± 0.05 and 1.30 ± 0.01 µM respectively. Structure activity relationship (SAR) was mainly based upon by bring about difference of substituents on phenyl rings. To confirm the binding interactions, molecular docking study was performed. Synthesized analogues were characterized through HREI-MS, 1H and 13C-NMR analysis.

The outbreak of novel coronavirus (COVID-19) infections in 2019 is in dire need of finding potential therapeutic agents. In this study, we used molecular docking to repurpose HIV protease inhibitors and nucleoside analogues for COVID-19, with evaluations based on docking scores calculated by AutoDock Vina and RosettaCommons. Our results suggest that Indinavir and Remdesivir possess the best docking scores, and comparison of the docking sites of the two drugs reveal a near perfect dock in the overlapping region of the protein pockets. After further investigation of the functional regions inferred from the proteins of SARS coronavirus, we discovered that Indinavir does not dock on any active sites of the protease, which may give rise to concern in regards to the efficacy of Indinavir. On the other hand, the docking site of Remdesivir is not compatible with any known functional regions, including template binding motifs, polymerization motifs and nucleoside triphosphate (NTP) binding motifs. However, when we tested the active form (CHEMBL2016761) of Remdesivir, the docking site revealed a perfect dock in the overlapping region of the NTP binding motif. This result suggests that Remdesivir could be a potential therapeutic agent. Clinical trials still must be done in order to confirm the curative effect of these drugs.

The details of antigen-antibody interactions and the identification of epitopes are critical for the development of monoclonal antibody drugs. Ab42 is a native human-derived anti-CFH monoclonal antibody. In this study, the interaction between antigen pCFH and antibody (Ab42) was theoretically demonstrated by molecular docking and MD simulation, combined with free energy calculation and computational alanine scanning (CAS), and key amino acids and epitopes were identified. Experimental alanine scanning (EAS) was then carried out to verify the results of the calculation, and our results indicated that Ab42 antibody forms hydrogen bonds and interacts hydrophobically with pCFH through the Tyr315, Ser100, Gly33, and Tyr53 residues on its CDR, while the main pCFH epitopes are located at the six sites of Pro441, Ile442, Asp443, Asn444, Ile447, and Thr448. In conclusion, this study has explored the mechanism of antigen-antibody interaction from both theoretical and experimental aspects, and our results have important theoretical significance for the design and development of relevant antibody drugs.

Background: COVID-19, a member of corona virus family is spreading its tentacles across the world due to lack of drugs at present. Associated with its infection are cough, fever and respiratory problems causes more than 15% mortality worldwide. It is caused by a positive, single stranded RNA virus from the enveloped coronaviruse family. However, the main viral proteinase (Mpro/3CLpro) has recently been regarded as a suitable target for drug design against SARS infection due to its vital role in polyproteins processing necessary for coronavirus reproduction.Objectives: The present in silico study was designed to evaluate the effect of Eucalyptol (1,8 cineole), a essential oil component from eucalyptus oil, on Mpro by docking study.Methods: In the present study, molecular docking studies were conducted by using 1-click dock and swiss dock tools. Protein interaction mode was calculated by Protein Interactions Calculator.Results: The calculated parameters such as RMSD, binding energy, and binding site similarity indicated effective binding of eucalyptol to COVID-19 proteinase. Active site prediction further validated the role of active site residues in ligand binding. PIC results indicated that, Mpro/eucalyptol complexes forms hydrophobic interactions, hydrogen bond interactions and strong ionic interactions.Conclusions: Therefore, eucalyptol may represent potential treatment potential to act as COVID-19 Mpro inhibitor. However, further research is necessary to investigate their potential medicinal use.

A derivative series of 3,4-dimethoxy-β-nitrostyrene were synthesized and identified including new compound 6. The effect of antimicrobial activity of 3,4-alkyloxy modification of β-nitrostyrene was investigated. A molecular docking was also performed to obtain information about their interactions with Protein Tyrosine Phosphatase 1B (PTP1B). PTP1B containing cysteine 215 and arginine 221 as essential active residues plays a key role in signaling pathways that regulate various cell functions of microorganisms, which also act as negative regulator in signaling pathways of insulin that are involved in type 2 diabetes and other metabolic diseases. Compound 5 and 6 were the most potent as fragment of PTP1B inhibitor based on molecular docking, but compound 5 was more effective against Candida albicans. These compounds interact with serine 216 and arginine 221 residues. However, further research is needed to investigate their potential medicinal use.

Phenol is added to acetophenone (methyl phenyl ketone) and to six of its halogenated derivatives in a supersonic jet expansion to determine the hydrogen bonding preference of the cold and isolated 1:1 complexes by linear infrared spectroscopy. Halogenation is found to have a pronounced effect on the docking site in this intermolecular ketone balance experiment. The spectra unambiguously decide between competing variants of phenyl group stacking due to their differences in hydrogen bond strength. Structures where the phenyl group interaction strongly distorts the hydrogen bond are more difficult to quantify in the experiment. For unsubstituted acetophenone, phenol clearly prefers the methyl side despite a predicted sub-kJ/mol advantage which is nearly independent of zero point vibrational energy, turning this complex into a challenging benchmark system for electronic structure methods which include long range dispersion interactions in some way.

Marburg virus disease (MVD) is a hemorrhagic fever and cause death up to 88% of people and is the same as Ebola virus, It is transmitted through skin contact or mucous membrane in the eyes, nose or mouth with blood or body fluids like urine, saliva sweat, feces and by object contaminated with body fluids. Despite these facts, yet there is no approved vaccine have been developed for the eradication of Marburg virus infections. Therefore, this study described a multi epitope-based peptide vaccine against Marburg virus viral protein 35, using several immunoinformatics tools combined with molecular docking studies. Utilizing Vaxijen 2.0 server, the V35 protein revealed to be antigenic with a score of 0.4316. Prediction of the T-cell and B-cell epitopes was then conducted. RTFDAFLGV epitope was found to be the most promising one with binding affinity to the highest numbers of MHC I alleles, a positive score in the Class I immunogenicity study and non-allergen. These results were further confirmed by the good interaction of RTFDAFLGV to the groove of HLA-A*02:01 with binding energy of -8.1 kcal/mole. Finally, the vaccine was cloned in silico to ensure its validity and efficiency of expression. To ensure its safety and immunogenic profile, in-vitro and in-vivo bioassays are recommended to confirm these findings.

This dissertation presents a method for the synthesis of substituted indoles bearing heterocyclic substituents onto the 3- position. The route for the synthesis of the heterocyclic substituents indoles starts from 3-acetyl indole nucleus depend on two parts. One part: Reaction of 3-acetylindole 1 with hydrazide compounds such as phenyl hydrazine, hydrazine hydrate, and thio-semicarbazide, to yield 3-(1-(2-phenylhydrazono) ethyl)-1H-indole 2, 3-(1-hydrazonoethyl)-1H-indole 6, and thiosemicarbazone 10 respectively. 3-(1-Hydrazonoethyl)-1H-indole 6 reacted with thiophene-2-carboxaldeyde, isatin and 3-acetyl indole. In the same way, 3-(1-(2-phenylhydrazono) ethyl)-1H-indole 2 reacted with thioglycollic acid, glycine and benzaldehyde. 3-Acetylindole 1 thiosemicarbazone reacted with acetic anhydride, piperidine, concentration of hydrochloric acid and thiophene-2-carboxaldeyde. Second part. Reaction of 3-acetyl indole 1 with amines compounds such as p-nitroaniline to formed Schiff base 15 which it reacted with thioglycollic acid to give compound 16. 3-Acetyl indole 1 reacted with ethylene diamine to afford bis imine indole to afford compound 17. The reports of this docking study revealed that the new compounds exhibit good antibacterial activity. The synthesized compounds screened in vitro for their antibacterial activity revealed remarkable inhibitory effects against the selected microorganisms. And also an anti-oxidant activity studying for some synthesized compounds. Structures of the newly synthesized compounds examination by spectral data (IR, 1H- NMR and 13C -NMR).

The outbreak of Coronavirus, as well as its emerging potential consequences, has become a global challenge worldwide, demanding effective and controlled therapeutic strategies. Potential drug candidates could achieve that with minimal toxicity. The current investigation selected 2-Deoxy-D-glucose prescribed by Defense Research and Development Organization (DRDO), India. The derivative and modified form was tested through in silico analysis against COVID-19 main protease complex with N3 inhibitor. The derived form of 2-Deoxy-D-glucose was generated by replacing the hydroxy group with a hydrogen atom, and Cypate 2-Deoxy-D-glucose was chosen as a derivative against the COVID-19 main protease complex. A molecular docking approach was adopted to identify the stable and competent form among the modified and derivative forms of 2-Deoxy-D-glucose based on binding energy. By further promoting the stabilized complex, these compounds' toxicity was also scrutinized through ADMET analysis to predict the potential candidate. The current investigation suggested that the modified version of 2-Deoxy-D-glucose was more stable with minimal toxicity against COVID-19 main protease.

The spread of the global COVID-19 pandemic, the lack of specific treatment and the urgent situation requires use of all resources to remedy this scourge. In the present study, using molecular docking, we identify new probable inhibitors of COVID-19 by molecules from Nigella sativa L, which is highly reputed healing herb in North African societies and both Islamic and Christian traditions. The discovery of the M^pro protease structure in COVID-19 provides a great opportunity to identify potential drug candidates for treatment. Focusing on the main proteases in CoVs (3CL^pro/M^pro) (PDB ID 6LU7 and 2GTB); docking of compounds from Nigella Sativa and drugs under clinical test was performed using Molecular Operating Environment software (MOE). Nigelledine docked into 6LU7 active site gives energy complex about -6.29734373 Kcal/mol which is close to the energy score given by chloroquine (-6.2930522 Kcal/mol) and better than energy score given by hydroxychloroquine (-5.57386112 Kcal/mol) and favipiravir (-4.23310471 kcal/mol). Docking into 2GTB active site showed that α- Hederin gives energy score about-6.50204802 kcal/mol whcih is better energy score given by chloroquine (-6.20844936 kcal/mol), hydroxychloroquine (-5.51465893 kcal/mol)) and favipiravir (-4.12183571kcal/mol). Nigellidine and α- Hederin appeared to have the best potential to act as COVID-19 treatment. Further, researches are necessary to testify medicinal use of identified and to encourage preventive use of Nigella Sativa against coronavirus infection.

[Co(AMPY)(DAPY)Cl2(H2O)].H2O (1) [Cu(AMPY)(DAPY)Cl2(H2O)].H2O (2) [Zn(AMPY)(DAPY)Cl2(H2O)] (3) were prepared from the ligands; AMPY = 2-amino-4-methylpyrimidine (L1), DAPY = 2,3-diaminopyridine (L2) and CoCl2.6H2O, CuCl2.2H2O and ZnCl2 in water/ethanol solutions and the three products characterized by elemental analysis, ultraviolet-visible spectroscopy (UV–Vis), Fourier-transform infrared spectroscopy (FT-IR), magnetic susceptibility, molar conductivity methods, and TGA analysis. The X-ray powder diffraction of the Co(II), Cu(II), and Zn(II) compounds showed that the geometry of monoclinic and SEM analysis revealed their morphology with a smooth surface. Molecular modeling was performed for all compounds using the density functional method DFT/B3LYP to study the structures and the frontier molecular orbitals (HOMO and LUMO). We have used Gaussian09 software for the calculations. In this study, different complexes were tested against Gram negative and Gram positive bacterial species to give insight into their broad-spectrum effects. The used pathogenic strains were two Gram positive species "Staphylococcus aureus and Micrococcus luteus" and two Gram negative species "Salmonella thyphimurium and Escherichia coli. The antifungal activity was evaluated against a pathogenic reference strain of the yeast Candida albicans. The antimicrobial and antioxidant assay results demonstrate that the tested compounds are effective against Gram positive and negative bacteria. Additionally, the compounds have an antifungal effect against Candida albicans with a maximum inhibitory zone of 2.5cm. The results demonstrated high antioxidant potential for the Zn(II) complex with a DPPH scavenging of 91.5%, however, the Cu(II) complex was low (16.5%). The data of docking with tyrosyl-tRNA synthetase presented that all compounds fit very well in the catalytic pockets of the proteins of the receptor.

As part of valorisation of agricultural waste into bioactive compounds, a series of structurally novel oleanolic acid ((3β-hydroxyolean-12-en-28-oic acid, OA-1)-phtalimidines (isoindolinones) conjugates 18a-v bearing 1,2,3-triazole moieties were designed and synthesized by treating a previously azide 4 prepared from OA-1 isolated from olive pomace (Olea europaea L.) with a wide range of propargylated phtalimidines using the Cu(I)-catalyzed click chemistry approach. OA-1 and its newly prepared analogues 18a-v were screened in vitro for their antibacterial activity against two Gram-positive bacteria, Staphylococcus aureus and Listeria monocytogenes; and two Gram-negative bacteria, Salmonella thyphimurium and Pseudomonas aeruginosa. Attractive results were obtained notably against L. monocytogenes. Compounds 18d, 18g and 18h exhibited the highest antibacterial activity when compared with OA-1 and other compounds in the series against tested pathogenic bacterial strains. Molecular docking study was performed to explore the binding mode of the most active derivatives against the target protein from L. monocytogenes. Results showed the importance of both hydrogen bonding and hydrophobic interactions with the target protein and are in favor to the experimental data.

Corona Virus Infectious Disease-2019 (COVID-19) outbreak originated recently at Wuhan, China in December 2019. It has already spread rapidly to more than 200 countries and has been declared a pandemic by WHO. It is caused by a beta-coronavirus named as SARS-CoV-2. There is no definitive cure, either drug or vaccine, to treat or prevent this viral disease. Recently, the crystal structure of the main protease M^pro has been determined. M^pro is responsible for the proteolytic maturation of the polyprotein essential for the viral replication and transcription, which makes it an important drug target. The discovery of new drug molecules may take years before getting to the clinics. So, considering urgency we performed molecular docking studies using FDA approved drugs to identify molecules that could potentially bind to the substrate-binding site and inhibit SARS-CoV-2 main protease (M^pro). We used the Glide module in Schrodinger software suite to perform molecular docking studies followed by MM-GBSA based energy calculations to score the hit molecules. Molecular docking and manual analysis suggest that several drugs may bind and potentially inhibit M^pro. We also performed molecular simulations studies for selected compounds to evaluate protein-drug interactions. Interestingly, we observed only one antiviral compound, Adefovir, in the top50 list of compounds. Considering bioavailability, lesser toxicity, route of administration some of the top-ranked drugs including lumefantrine (antimalarial), dipyridamole (coronary vasodilator), dihydroergotamine (used for treating migraine), hexoprenaline (anti- asthmatic), riboflavin (vitamin B2) and pantethine (vitamin B5) may be taken forward for further in vitro and in vivo experiments to investigate their therapeutic potential.

The article describes facile one-pot, hi-yielding reactions to synthesize substituted 3,4-dimethyl-1H-pyrrole-2-carboxamide (3a–m) and carbohydrazide analogues (5a–l) as potential antifungal and antimicrobial agents. The structural integrity and purity of the synthesized compounds were assigned based on appropriate spectroscopic techniques. Synthesized compounds were assessed in vitro for antifungal and antibacterial activity. The compound 5h, 5i and 5j were found to be the most potent against A. fumigatus, with MIC value of 0.031 mg/mL. The compound 5f bearing a 2,6-dichloro group on the phenyl ring was found to be the most active broad spectrum antibacterial agent with MIC value of 0.039 mg/mL. The mode of action of the most promising antifungal compounds (one representative from each series; 3j and 5h) was established by their molecular docking to the active site of sterol 14α-demethylase. Molecular docking studies revealed a highly spontaneous binding ability of the tested compounds in the access channel away from catalytic heme iron of the enzyme, which suggested that the tested compounds inhibit this enzyme and would avoid heme iron related deleterious side effects observed with existing antifungal compounds.

Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options and a poor prognosis. Cancer stem cells (CSCs) have emerged as a critical factor in GBM resistance and management, contributing to tumor growth, heterogeneity, and immunosuppression. The transcription factor FOXM1 has been identified as a key player in the progression, spread, and therapy resistance of various cancers, including GBM. In this study, researchers conducted structure-based in silico screening to identify natural compounds that could target the DNA-binding domain (DBD) of the FOXM1 protein. Through molecular docking analyses, identified Silybin B as a potential inhibitor of FOXM1, exhibiting strong interaction with the protein. MD simulations were performed to validate the binding stability of the FOXM1-Silybin B complex. The study provides valuable insights into the potential of Silybin B as a FOXM1 inhibitor and its ability to induce senescence in GBM stem cells. These findings contribute to the development of structure-based design strategies for FOXM1 inhibitors and innovative therapeutic approaches for the treatment of Glioblastoma.

Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In search for therapeutic alternatives to treat the cancer disease, a se-ries of hybrid pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones, 5a-h, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide 4 with a series of arylaldehydes in EtOH, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that 5a, 5e, 5g, and 5h were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, 5a, 5e, 5g, and 5h were evalu-ated for their binding interactions with two well-known anticancer targets, namely the epider-mal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of 5a, 5e, 5g, and 5h towards EGFR. CD experi-ments suggested 5a as a stabilizer agent of the G-quadruplex from the KRAS oncogene promot-er. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hy-drazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds.

Cervical cancer is a significant global health concern, with human papillomavirus (HPV) infection being a crucial risk factor. Photodynamic therapy (PDT) is an attractive, minimally invasive treatment for HPV-related cervical lesions, which uses photosensitizers and light to selectively de-stroy abnormal cells. We aim to provide an overview of the various sorts of dyes that are utilized in PDT for decreasing the incidence and mortality of cervical cancer. Besides, the article discusses ongoing clinical trials for PDT in low-grade squamous intraepithelial neoplasia (LSIL) and high-grade squamous intraepithelial lesions (HSIL), as well as preclinical approaches for PDT in cervical cancer using various dyes. Moreover, it highlights potential dyes for PDT, examine them in in-silico condition, their pros and cons and also the solutions for enhancing their anticancer com-patibility. We also display that PDT is a promising therapeutic strategy for the diagnosis and treatment of HPV-associated cervical lesions. Moreover, it shows that using different classes of dyes improves the anticancer effects of PDT. Finally, among all dyes which are used in PDT, Fullerene demonstrated high tendency to over expressed receptors in cervical cancer cells and seems to be a proper candidate for be used in PDT more than before, but further research is necessary to assess its long-term efficacy and safety.

Natural and synthetic small molecules from the NCI Developmental Therapeutics Program (DTP) were employed in molecular dynamics-based docking with DNA repair proteins whose RNA-Seq based expression was associated with overall cancer survival (OS) after adjustment for the PCNA metagene. The compounds employed were required to elicit a sensitive response (vs. resistance) in more than half of the cell lines tested for each cancer. Methodological approaches included peptide sequence alignments and homology modeling for 3D protein structure determination, ligand preparation, docking, toxicity and ADME prediction. Docking was performed for unique lists of DNA repair proteins which predict OS for AML, cancers of the breast, lung, colon, and ovaries, GBM, melanoma, and renal papillary cancer. Results indicate hundreds of drug-like and lead-like ligands with best-pose binding energies less than -6 kcal/mol. Ligand solubility for the top 20 drug-like hits approached lower bounds, while lipophilicity was acceptable. Most ligands were also blood-brain barrier permeable with high intestinal absorption rates. While the majority of ligands lacked positive prediction for Herg channel blockage and Ames carcinogenicity, there was considerable variation for predicted fathead minnow, honey bee, and Tetrahymena pyriformis toxicity. The computational results suggest the potential for new targets and mechanisms of repair inhibition and can be directly employed for in vitro and in vivo confirmatory laboratory experiments to identify new targets of therapy for cancer survival.

The aim of the study was to determine the possibility of suppression of the prostaglandin synthesis by new derivatives of N-phenylanthranilic acids; they inhibit the activity of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme using the method of a flexible molecular docking. For the docking studies the crystallographic structural models with high resolution from Protein Data Bank were used: mPGES-1 in the complex with glutathione (pdb code 4AL0). A flexible molecular docking was carried out using the Molecular Operating Environment (MOE) software package. According to the results of the docking studies four scoring functions were calculated (Affinity dG Scoring, Alpha HB Scoring, London dG Scoring, GBVI/WSA dG Scoring). The values of the scoring functions calculated indicate the thermodynamic probability and energy favorability of forming complexes between molecules of the substances under research and the specified receptor, in which arrangement of ligands in the active site of the receptor and residues of amino acids of side chains are of similar geometry and types of binding of the known inhibitors of mPGES-1 determined on the basis of the crystallographic studies.

Aims: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. This paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 co-crystallized with COVID-19 spike protein. Methods: First, the starting point was ACE2 inhibitors and their structure-activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. In parallel, at all stages, authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 co-crystallized with COVID-19 spike protein. Results: Carnosine emerged as the best known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the co-crystallized protein structure, carnosine bind with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 co-crystallized with COVID-19 spike protein and hence could offer potential mitigating effect against current COVID-19 pandemic.

The Novel Coronavirus (COVID-19) is a positive-sense single-stranded RNA ((+)ssRNA) virus. The COVID-19 Main Proteases play very important role in the propagation of the Novel Coronavirus (COVID-19). It has already killed more than 8000 people around the world and thousands of people are getting infected every day. Therefore, it is very important to identify a potential inhibitor against COVID-19 Main Proteases to inhibit the propagation of the Novel Coronavirus (COVID-19). We have applied a drug repurposing approach of computational methodology, depending on the synergy of molecular docking and virtual screening techniques, aimed to identify possible potent inhibitors against Novel Coronavirus (COVID-19) from FDA approved antiviral compounds and from the library of active phytochemicals. On the basis of recently resolved COVID-19 Main Protease crystal structure (PDB:6LU7), the library of 100 FDA approved antiviral compounds and 1000 active components of Indian Medicinal Plants extracted for screening against COVID-19 Main Protease. The compounds were further screened using Pyrex virtual screening tool and then best inhibitors, top 19 compounds optimally docked to the COVID-19 Main Protease structure to understand the participation of specific amino acids with inhibitors at active sites. Total 19 best compounds were identified after screening based on their highest binding affinity with respect to the other screened compounds. Out of 19, 6 best compounds were further screened based on their binding affinity and best ADME properties. Nelfinavir exhibited highest binding energy -8.4 kcal/mol and strong stability with the TRP207, ILE281, LEU282, PHE3, PHE291, GLN127, ARG4, GLY283, GLU288, LYS5, LYS137, TYR126, GLY138, TYR126, SER139 and VAL135 amino acid residues of COVID-19 Main Protease participating in the interaction at the binding pocket. In addition to Nelfinavir (-8.4), Rhein (-8.1), Withanolide D (-7.8), Withaferin A (-7.7), Enoxacin (-7.4), and Aloe-emodin (-7.4) also showed good binding affinity and best ADME properties. Our findings suggest that these compounds can be used as potential inhibitors against COVID-19 Main Protease, which could be helpful in inhibiting the propagation of the Novel Coronavirus (COVID-19). Moreover, further in vitro and in vivo validation of these findings would be very helpful to bring these inhibitors to next level study.

According to our previous investigation the total methanol extract from Graptopetalum paraguayense E. Walther demonstrates a significant inhibitory effect on HSV-1. To clarify what causes this inhibitory activity on HSV-1, a metabolic profile of the plant was performed. Three main fractions: non-polar substances, polar metabolites and phenolic compounds were obtained and GC-MS analysis was carried out. Since it is well known that phenolic compounds show a significant anti-herpes effect and that viral DNA polymerase (DNApol) appears to play a key role in HSV virus replication, we present a docking and quantum-chemical analysis of the binding of these compounds to viral DNApol amino acids. Fourteen different phenolic acids found by GS/MS analyses, were used in molecular docking simulations. According to the interaction energies of all fourteen ligands in the DNApol pockets based on docking results, DFT calculations were performed on the five optimally interacting with the receptor acids. It was found that hydroxybenzoic acids from phenolic fraction of Graptopetalum paraguayense E. Walther show a good binding affinity to the amino acids from the active site of the HSV DNApol, but significantly lower than that of acyclovir. The mode of action on virus replication of acyclovir (by DNApol) is different from that of the plant phenolic acids one, probably.

Structurally related 7-acetyl-2-aryl-5-bromoindoles 2a–d and the 7-acetamido-2-aryl-5-bromoindoles 4a–d as well as their corresponding 3-trifluoroacetyl–substituted derivatives 5a–d and 5e–h were evaluated for potential antigrowth effect in vitro against the human lung cancer (A549) and cervical cancer (HeLa) cells. All of the 3-trifluoroacetyl–substituted 7-acetamido-2-aryl-5-bromoindoles 5e–h were found to be more active against both cell lines when compared to the chemotherapeutic drug, Melphalan. The most active compound 5g induced apoptosis in a caspase dependent manner for both cell lines. Compounds 5e–h were found to significantly inhibit tubulin polymerization. Molecular docking of 5g into the colchicine-binding site suggests that the compounds bind to tubulin by different type of interactions including pi-alkyl, amide-pi stacked and alkyl interactions as well as hydrogen bonding with the protein residues to elicit anticancer activity.

2-(Adamantan-1-yl)-2H-isoindole-1-carbonitrile (1) has been identified as a neurobiological fluorescent ligand that may be used to develop receptor and enzyme binding affinity assays. Compound 1 was synthesised using an optimised microwave irradiation reaction and crystallised from ethanol. Crystallization occurred in the orthorhombic space group P212121 with unit cell parameters: a = 6.4487(12) Å, b = 13.648(3) Å, c = 16.571(3) Å, V = 1458(5) Å3, Z = 4. Density functional theory (DFT) (B3LYP/6-311++G (d,p)) calculations of 1 were carried out. Results showed that the optimised geometry is similar to the crystal structure parameters with a root-mean-squared deviation of 0.143 Å. Frontier molecular orbital energies and net atomic charges are discussed with a focus on potential biological interactions. Docking experiments within the active site of the neuronal nitric oxide synthase (nNOS) protein crystal structure were carried out and analysed. Important binding interactions between the DFT optimised structure and amino acids within the nNOS active site were identified that explain the strong NOS binding affinity reported. Fluorescent properties of 1 were studied using aprotic solvents of different polarities. Compound 1 showed the highest fluorescence intensity in polar solvents with excitation and emission values of 336 nm and 380 nm, respectively.

A series of novel substituted isoxazolidine derivatives was synthesized through 1,3-dipolar cycloaddition reactions of α-aryl-N-methyl nitrones with various ethylene moieties, resulting in the formation of isoxazolidine derivatives. The structures of the synthesized compounds were characterized using spectroscopic methods. The [3+2] cycloaddition (32CA) reactions of α-aryl-N-methyl nitrones with diverse ethylene substituents were computed employing Density Functional Theory (DFT) at the B3LYP/6–31G(d) level, upgrading bond parameters. An investigation of the electron localization function (ELF) unveiled the zwitterionic nature of α-aryl-N-methyl nitrones, devoid of pseudoradical or carbenoid centers. Utilization of CDFT indices enabled the prediction of global electronic flux from the strongly nucleophilic α-aryl-N-methyl nitrones to the varied electrophilic ethylene functionalities. Molecular docking and molecular dynamics simulations were conducted on the isoxazolidine derivatives against the EGFR receptor (PDB: 4ZAU). In silico assessment of the synthesized isoxazolidines involved molecular docking, wherein the compound with the highest docking score was subjected to molecular dynamics simulations. Compound 11a, out of the thirty isoxazolidine derivatives, displayed the most substantial binding energy, yielding a g score of -6.57 kcal/mol. These observations highlighted the functional role of amide NH2 and NO2 in the binding process with the target protein, influencing its activity. Furthermore, prediction of ADME drug-likeness properties was performed to identify a suitable candidate.

The current study describes the preparation of chitosan nanoparticles (CNPs) using hydroxychloroquine (HCQ), widely used in traditional medicine due to its diverse phar-macological and medicinal uses. This work aims to combine the HCQ drug with CS NPs to generate a novel nanocomposite with improved characteristics and bioavailability. HCQ@CS NPs is roughly shaped like roadways and has a smooth surface with an average size of 159.3±7.1 nm, a PdI of 0.224±0.101, and a zeta potential of +46.6±0.8 mV. To aid in the development of pharmaceutical systems for use in cancer therapy, the binding mech-anism and affinity of the interaction between HCQ and HCQ@CS NPs and BSA were ex-amined using stopped-flow, other spectroscopic approaches, supplemented by molecular docking analysis. HCQ and HCQ@CS NPs binding with BSA is driven by a ground-state complex formation that may be accompanied by a non-radiative energy transfer process, and binding constants indicated that HCQ@CS NPs-BSA was more stable than HCQ-BSA. The stopped-flow analysis demonstrated that, in addition to increasing BSA affinity, the nano formulation HCQ@CS NPS changes the binding process and may open up new routes for interaction. Docking experiments verified the development of the HCQ-BSA complex, with HCQ binding to the site I on the BSA structure, primarily with the amino acids Thr 578, Gln 579, Gln 525, Tyr 400, and Asn 404. Furthermore, the nano-formulation HCQ@CS NPS not only increased cytotoxicity against the A549 lung cancer cell line (IC50 = 28.57±1.72 g/ml) compared to HCQ (102.21±0.67) g/ml), but also exhibited higher anti-bacterial activity against both Gram-positive and Gram-negative bacteria when compared to HCQ and chloramphenicol which in agreement with the binding constants. The nano formulation developed in this study may offer a viable therapy option for A549 lung cancer.

Mink astrovirus infection remains a poorly understood disease entity, and the aetiological agent itself causes disease with a heterogeneous course, including gastrointestinal and neurological symptoms. This paper presents cases of astrovirus infection in mink from continental Europe. RNA was isolated from the brains and intestines of animals showing symptoms typical of shaking mink syndrome (n = 6). RT-PCR was used to detect astrovirus genetic material, and the reaction products were separated on a 1% agarose gel. The specificity of the reaction was confirmed by sequencing all samples. The presence of astrovirus RNA was detected in each of the samples tested. Sequencing and bioinformatic analysis indicated the presence of the same variant of the virus in all samples. Comparison of the variant with the sequences available in bioinformatics databases confirmed that the Polish isolates form a separate clade, closely related to Danish isolates. The similarity of the Polish variant to those isolated in other countries ranged from 2.4% (in relation to Danish isolates) to 7.1% (in relation to Canadian isolates). Phylogenetic relationships between variants appear to be associated with the geographic distances between them. To our knowledge, this work describes the first results on the molecular epidemiology of MAstV in continental Europe. The detection of MAstV in Central Europe indicates the need for further research to broaden our understanding of the molecular epidemiology of MAstV in Europe.

Herein, we are proposing two chalcone molecules, (E)-1-(4-methoxyphenyl)-3-(p-tolyl) prop-2-en-1-one and (E)-3-(4-hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl) prop-2-en-1-one, based on the anticancer bioactive molecule Xanthohumol, which are suitable for further in vitro and in vivo studies. Their ability to create stable complexes with the antiapoptotic X-linked IAP (XIAP) protein makes them promising anticancer agents. The calculations were based on ligand-based and structure-based virtual screening combined for the pharmacophore built. Additionally, the structures passed Lipinski's rule for drug use, and their reactivity was confirmed using density functional theory studies. The candidates were chosen between 10639400 compounds, and the docking protocols were evaluated using molecular dynamics simulations.

Leishmaniasis is a group of neglected infectious, non-contagious diseases caused by parasites of the Leishmania genus which affects millions of people worldwide. The drugs available for its treatment, especially in cases of visceral leishmaniasis, are old, outdated, have serious side effects and in many cases are ineffective due to the emergence of resistant strains. In this context, the search for new candidates for more effective and safer drugs which can become new therapeutic alternatives is a constant need. In this work, 10 new chalcones were synthesized in high yields through Claisen-Schmidt condensation and were evaluated in vitro against Leishmania infantum promastigotes and amastigotes. CP04 and CP06 compounds were the most promising, respectively showing IC50 values = 13.64 ± 0.25 and 11.19 ± 0.22 against promastigotes, and IC50 = 18.92 ± 0.05 and 22.42 ± 0.05 against amastigotes. The compounds did not show cytotoxicity in erythrocytes, showing selectivity indexes greater than 74 and 90. Molecular docking studies carried out under the sterol 14-alpha demethylase (CYP-51) (PDB: 3L4D) and trypanothione reductase (PDB: 5EBK) enzymes from L. infantum evidenced the great affinity of the CP04 molecule for these targets, showing Moldock score values of -94.0758 and -50.5692 KJ/mol-1, with these values being much lower than the co-crystallized ligand energies. Molecular dynamics simulations demonstrated great stability of CP04 in its targets, thus indicating a real interaction possibility. Our findings confirm the potential that chalcones have as candidates for anti-leishmania drugs, and suggest that the CP04 compound may become a promising drug candidate to design and develop novel chalcone-based analogs for leishmaniosis therapy.

Oleanolic acid (OA) being the ubiquitous compound in the plant kingdom is studied for both the neuroprotective and neurotoxic properties. The mechanism of acetylcholinesterase (AChE) inhibitory potential of OA is investigated using the molecular dynamic simulations (MD) and docking as well as membrane-like and in vitro tests. There are also applied SH-SY5Y human neuroblastoma cells as well as in vivo on the zebrafish tests. The inhibitory potential towards the AChE enzyme is examined using the TLC-bioautography assay (the IC50 value is 9.22 μM). The CH- interactions between the central fragment of the ligand molecule and the aromatic cluster created by the His440, Phe288, Phe290, Phe330, Phe331, Tyr121, Tyr334, Trp84 and Trp279 side chains are observed. The in vitro tests carried out on the SH-SY5Y cells indicates that the viability rate is reduced to 71.5%, 61%, and 43% at the concentrations of 100 µg/mL, 300 µg/mL, and 1000 µg/mL, respectively after 48 hours of incubation whereas cytotoxicity against the tested cell line with the IC50 value is 714.32 ± 32.40 µg/mL. The in vivo tests on the zebrafish prove that there is no difference between the control and experimental groups as regards the mortality rate and morphology (P>0.05).

Molecular classifications of colorectal cancer (CRC) are benefitting cancer research by providing insights into subtype-specific disease prognosis and better therapeutic intervention. So far different conventional DNA markers such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), chromosomal instability (CIN), and BRAF and KRAS mutations have been used to classify CRC patients but have not shown promising prognostic values. Here, for the first time, we show classification of CRC tumors from Saudi Arabian patients based on gene expression profile (GEP). An existing method of CRC subtyping has been applied to the GEP of tumors from Saudi CRC patients. Survival analysis was carried out on predicted CRC subtypes. In-silico functional analyses were conducted on the gene signature used for subtype prediction. The predicted subtypes showed distinct but statistically insignificant overall survival distribution (log-rank test, p = 0.069). Comparison of predicted subtypes in Saudi CRC patients with that of the French one showed significant dissimilarity in the two populations (Chi-square test, p = 0.0091). Functional analyses of the gene signature used for subtyping suggest their association with “cancer” and “gastrointestinal diseases”. Most of the signature genes were found differentially expressed in CRC tumors compared to adjacent normal tissues. Such a classification framework might help improve the treatment of colorectal cancer patients.

Amorphous solid dispersions are considered a promising formulation strategy for the oral delivery of poorly soluble drugs. The limiting factor for the applicability of this approach is the physical (in)stability of the amorphous phase in solid samples. Minimizing the risk of reduced shelf life for a new drug by establishing a suitable excipient/polymer-type from first principles would be desirable to accelerate formulation development. Here we perform Molecular Dynamics simulations to determine properties of blends of eight different polymer-small molecule drug combinations for which stability data is available from a consistent set of literature data. We calculate thermodynamic factors (mixing energies) as well as mobilities (diffusion rates and roto-vibrational fluctuations). We find that either of the two factors, mobility and energetics, can determine the relative stability of the amorphous form for a given drug. Which factor is rate limiting depends on physico-chemical properties of the drug and the excipients/polymers. The methods outlined here can be readily employed for an in-silico pre-screening of different excipients for a given drug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development.

Background: Selectively targeting dopamine receptors has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases evolving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like receptors). Fifteen structurally diverse ligands were docked to these models. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for DR sub-type specificity. Results: We showed that the number of conformations for a receptor:ligand complex was associated to unspecific interactions > 2.5 Å and hydrophobic contacts, while the decoys binding energy was influenced by specific electrostatic interactions. Known residues such as 3.32Asp, the serine microdomain and the aromatic microdomain were found interacting in a variety of modes (HB, SB, π-stacking). Purposed TM2-TM3-TM7 microdomain was found to form a hydrophobic network involving Orthosteric Binding Pocket (OBP) and Secondary Binding Pocket (SBP). T-stacking interactions revealed as especially relevant for some large ligands such as apomorphine, risperidone or aripiprazole. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, key for the design of more specific ligands.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack treatment options. Gene alterations (GAs) are frequently observed in PDAC; some of which are considered for molecular targeted therapies (MTTs), with potential clinical benefits and im-proved outcomes. However, the applicability of molecular profiling (MP) for precision medicine in PDAC remains to be demonstrated. Methods: We conducted a retrospective analysis of all patients, aged ≥18 years with histologi-cally confirmed PDAC, who underwent tumor MP between 2010 and 2020 in our institution as part of personalized medicine trials. The primary study endpoint was overall survival (OS), and (minimal follow-up was 6 months after MP. Results: Of 115 eligible patients, MP was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Based on ESCAT classification, actionable GAs were found in 29 patients (28%), involving mainly BRCA1 or BRCA2 (5 [18%]), HER2 (5 [18%]), MTAP (5 [18%]), and FGFR (3 [11%]). Only 12 of these 29 patients (41%, or 10% of the whole population) received MTTs, with a median progression-free survival of 1.6 months. Median OS was 19 months in patients with actionable GAs treated with MTTs (n=12 [11.8%]), 14 months in patients with actionable GAs treated with standard therapies (n=17 [16.7%]), and 17 months in patients without actionable GAs treated with standard therapies (n=73 [71.5%]; p=0.26). The absence of liver metastases was associated with better OS (HR=0.471, p=0.01). The highest OS following MTT was observed in patients with BRCA mutations treated with olaparib. Interpretation: Actionable GAs were found in more than a quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study with limited patient numbers. However, selected GA/MTT combinations (e.g., BRCA mutations/olaparib) were associated with a better outcome.

A series of 2-phenylamino-3-acyl-1,4-naphtoquinones were evaluated regarding their in vitro antiproliferative activities using DU-145, MCF-7 and T24 cancer cells. Such activities were discussed in terms of molecular descriptors like half-wave potentials, hydrophobicity and molar refractivity. Compounds 4 and 11 display the highest antiproliferative activity against the three cancer cells, therefore, they were subject to further studies. The in silico prediction of drug likeness, using pkCSM and SwissADME explorer online, shows that compound 11 is a suitable lead molecule to be developed. Furthermore, the expression of some key genes was studied in DU-145 cancer cells. They include genes involved in apoptosis (Bcl-2), tumor metabolism regulation (mTOR), redox homeostasis (GSR), cell cycle regulation (CDC25A), cell cycle progression (TP53), epigenetic (HDAC4), cell-cell communication (CCN2) and inflammatory pathways (TNF). Compound 11 displays an interesting profile because among these genes, mTOR was significantly less expressed as compared to control conditions. Molecular docking show that compound 11 has good affinity with mTOR, unraveling a potential inhibitory effect on this protein. Due to the key role of mTOR on tumor metabolism, we suggest that impaired DU-145 cells proliferation by compound 11 is caused by a reduced mTOR expression (less mTOR protein) and inhibitory activity on mTOR protein.

Melatonin is a hormone used for treating several disorders. However, its oral administration is problematic due to the variable absorption and extensive first-pass metabolism. The topical application of this drug does not present these disadvantages and can be used for therapeutic and skin protection purposes. The adsorption and release of melatonin in the montmorillonite clay was investigated experimentally and theoretically. The drug-clay interaction products were prepared and characterized, showing a modified and improved diffusion and release of melatonin. The crystal structure and spectroscopic properties of melatonin and melatonin-water-mineral materials were studied by molecular modeling, finding that the adsorption of this drug is energetically favourable, and the results were consistent with the experimental data. Ab initio molecular dynamics simulations with the metadynamics methodology showed the release of melatonin from the confined interlayer nanospace of montmorillonite to the liquid bulk water with a 20 kcal/mol free energy barrier.

Salmonella, especially invasive non-typhoidal Salmonella (iNTS) are responsible for developing various invasive diseases, and possess higher mortality rate, due to their higher antibiotic resistance profile than the other bacteria. Therefore, the present study was concerned to develop epitope based peptide vaccine against iNTS species as a successive and substitute protective measures. The study considered comprehensive Immunoinformatic approaches, followed by molecular docking and molecular dynamics simulation to predict the efficient vaccine candidate T cell and B cell epitopes, based on the outer membrane proteins. The study identified two best epitopes YGIFAITAL and KVLYGIFAI from total iNTS outer membrane proteins, which showed higher immunity, non-allergenicity, non-toxicity and also showed higher conservancy and population coverage values. Both epitopes showed higher binding affinity and stability towards HLA-C* 03:03. The MM-PBSA binding free energy showed the YGIFAITAL epitope binds more tightly with both MHC-I and MHC-II molecules. The total contact, H-bond analysis and RMSF results also validate the efficiency of these epitopes as vaccine candidate. The projected B cell epitopes AAPVQVGEAAGS, TGGGDGSNT and TGGGDGSNTGTTTT showed higher antigenicity. Overall, the study concluded that these epitopes can be considered as the potential vaccine candidate to make a successive vaccine against iNTS species. However, this result further needs to be validate by wet lab research to make successive vaccine with these projected epitopes.

Ubiquitin-specific protease 14 (USP14) is a member of the Deubiquitinating enzymes (DUBs) involved in disrupting the regulation of the ubiquitin-proteasome system, responsible for the degradation of impaired and misfolded proteins which is an essential mechanism in eukaryotic cells. The involvement of USP14 in cancer progression and neurodegenerative disorders has been reported. Thereof USP14 is a prime therapeutic target; hence, designing efficacious inhibitors of USP14 is central in curbing these conditions. Herein, we relied on structural bioinformatics methods incorporating molecular docking, Molecular Mechanics Generalized Born Surface Area (MM-GBSA), Molecular dynamics simulation (MD simulation) and ADME to identify potential allosteric USP14 inhibitors. A library of over 733 compounds from the PubChem repository with >90% match to the IU1 chemical structure was screened in a multi-step framework to attain prospective drug-like inhibitors. Two potential lead compounds (CID 43013232 and CID 112370349) were shown to record better binding affinity compared to IU1, but with subtle difference to IU1-47, a 10-fold potent compound when compared to IU1. The stability of the lead molecules complexed with USP14 was studied via MD simulations. The molecules were found to be stable within the binding site throughout the 50ns simulation time. Moreover, the protein-ligand interactions across the simulation run time suggest Phe331, Tyr476, and Gln197 as crucial residues for USP14 inhibition. Furthermore, in silico pharmacological evaluation revealed the lead compounds as pharmacological sound molecules. Overall, the methods deployed in this study revealed two novel candidates that may show selective inhibitory activity against USP14, which could be exploited to produce potent and harmless USP14 inhibitors.

Molecular dynamics(MD) simulations are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals the solvent structure and preferential interaction sites (hot spots) on the protein surface. This information is largely transferable across all classes of protein ligands (from water to drugs) and can be used very effectively to understand ligand recognition and improve the predictive capability of well-established methods such as molecular docking. MD simulations for protein and drug or drug-like compounds are now being used but are still computationally expensive and can only be applied to specific cases. On the other hand, MDmix simulations can now be used in SBDD and we will describe the latest developments and implementations. We expect to see an increase in the application of these techniques to a plethora of protein targets to identify new drug candidates with the advent of new tools and faster computers.

The increasingly common occurrence of antibiotic-resistant bacteria has become an urgent public health issue. There are currently some infections without any effective treatment, which require new therapeutic strategies. An attractive alternative is the design of compounds capable of disrupting bacterial communication known as quorum sensing (QS). In gram-negative bacteria, such communication is regulated by acyl-homoserine lactones (AHLs). QS allows bacteria to proliferate before expressing virulence factors. Our group previously reported that hexyloxy phenyl imidazoline (9) demonstrated 71% inhibitory activity of QS at 100 µM (IC50=90.9 µM) in Chomobacterium violaceum, a gram-negative bacterium. The aim of the present study was to take 9 as a lead compound to design and synthesize three 2-imidazolines (13-15) and three 2-oxazolines (16-18), to be evaluated as quorum sensing inhibitors on C. violaceum CV026. We were looking for compounds with a higher affinity towards the Cvi receptor of this bacterium and the ability to inhibit QS. The binding mode of the test compounds on the Cvi receptor was explored with docking studies and molecular dynamics. It was found that 8-pentyloxyphenyl-2-imidazoline 13 reduced the production of violacein (IC50=56.38 µM) without affecting bacterial growth, suggesting inhibition of quorum sensing. Indeed, compound 13 is apparently one of the best QS inhibitors known to date. Molecular docking revealed the affinity of compound 13 for the orthosteric site of the N-hexanoyl homoserine lactone (C₆-AHL) on the CviR protein. Ten aminoacid residues in the active site of C₆-AHL interacted with 13, and 7 of these are the same as those interacting with AHL. Contrarily, 8-octyloxyphenyl-2-imidazoline 14, 8-decyloxyphenyl-2-imidazoline 15 and 9-decyloxyphenyl-2-oxazoline 18 bound only to an allosteric site and thus did not compete with C₆-AHL for the orthosteric site.

Caveolin-1 (Cav-1) is 22 kDa caveolae protein, acts as a scaffold within caveolar membranes. It interacts with alpha subunits of G-protein and thereby regulates their activity. Earlier studies reported elevated or up-regulated levels of caveolin-1 in the serum of prostate cancer patients. Secreted Cav-1 promotes angiogenesis, cell proliferation and anti-apoptotic activities in prostate cancer patients. Cav-1 upregulation is mainly related to prostate cancer metastasis. Keeping above facts in view, the present study was designed to explore Cav-1 as a target for prostate cancer therapy using computational approach. Molecular docking, structural base molecular modelling and molecular dynamics simulations were performed to investigate Cav-1 inhibitors. A predictive model was generated and validated to establish a stable structure. ZINC database of biogenic compounds was used for induced fit docking (IFD) and high throughput virtual screening. The H-bond interactions of the compounds with active site residues of Cav-1 were estimated by IFD and 100 ns long molecular dynamic simulations. The reported compounds showed significant binding and thus can be considered as potent therapeutic inhibitors of Cav-1. This study provides a valuable insight into biochemical interactions of Cav-1 for therapeutic applications and warrants for experimental validation of the predicted ‘active(s)’.

We extend a previously developed model for the Stark resonances of the water molecule. The method employs a partial-wave expansion of the single-particle orbitals using spherical harmonics. To find the resonance positions and decay rates, we use the exterior complex scaling approach which involves the analytic continuation of the radial variable into the complex plane and yields a non-hermitian Hamiltonian matrix. The real part of the eigenvalues provides the resonance positions (and thus the Stark shifts), while the imaginary parts $-\Gamma/2$ are related to the decay rates $\Gamma$, i.e., the full-widths at half-maximum of the Breit-Wigner resonances. We focus on the three outermost (valence) orbitals, as they are dominating the ionization process. We find that for forces directed along the three Cartesian co-ordinates, the fastest ionizing orbital always displays a non-monotonic Stark shift. For the case of fields along the molecular axis we show results as a function of the number of spherical harmonics included ($\ell_{\max}=3,4$). Comparison is made with total molecule resonance parameters from the literature obtained with Hartree-Fock and coupled cluster methods.

Biological membranes are fascinating. Santiago Ramón y Cajal, who received the Nobel prize in 1906 together with Camillo Golgi for their work on the nervous system, wrote “[..]in the study of this membrane[..] I felt more profoundly than in any other subject of study the shuddering sensation of the unfathomable mystery of life”[1]. The visualization and conceptualization of these biological objects have profoundly shaped many aspects of modern biology, drawing inspiration from experiments, computer simulations, as well as from the imagination of scientists and artists. The aim of this review is to provide a fresh look on current ideas of biological membrane organization and dynamics by discussing selected examples across fields [1] The full quotation is “I must not conceal the fact that in the study of this membrane I for the first time felt my faith in Darwinism (hypothesis of natural selection) weakened, being amazed and confounded by the supreme constructive ingenuity revealed not only in the retina and in the dioptric apparatus of the vertebrates but even in the meanest insect eye. There, in fine, I felt more profoundly than in any other subject of study the shuddering sensation of the unfathomable mystery of life.” from the autobiography Recollections of My Life.

Organic-organic interactions play important roles in the secondary organic aerosol formation, but the interactions are complex and poorly understood. Here we use environmental molecular beam experiments combined with molecular dynamics simulations to investigate the interactions between methanol and nopinone, as atmospheric organic proxies. In the experiments, methanol monomers and clusters are sent to collide with three types of surfaces, i.e., graphite, thin nopinone coating on graphite and multilayer surfaces, at temperatures between 140 K and 230 K. Methanol monomers are efficiently scattered from the graphite surface, whereas the scattering is substantially suppressed from nopinone surfaces. The desorption from the three surfaces is similar, suggesting that all the surfaces have weak or similar influences on the methanol desorption. The molecular dynamics results show that upon collisions the methanol clusters shatter, and the shattered fragments quickly diffuse and recombine to clusters. The desorption involves a series of processes, including detaching from clusters and desorbing as monomers. The experimental results also show that all trapped methanol molecules completely desorb within a short experimental time scale at temperatures of 180 K and above. At lower temperatures, the desorption rate decreases, and a long experimental time scale is used to resolve the desorption, where three desorption components are identified. The fast component is beyond the experimental detection limit. The intermediate component exhibits multi-step desorption character and has an activation energy of E_a = 0.18 ± 0.03 eV, in good agreement with simulation results. The slow desorption component is related to diffusion processes due to the weak temperature dependence.

Kidneys of mice, rats and humans possess progenitors that maintain daily homeostasis and take part in endogenous regenerative processes following injury, owing to their capacity to proliferate and differentiate. In the glomerular and tubular compartments of the nephron, consistent studies demonstrated that well-characterized, distinct populations of progenitor cells, localized in the parietal epithelium of Bowman capsule and scattered in the proximal and distal tubules, could generate segment-specific cells in physiological conditions and following tissue injury. However, defective or abnormal regenerative responses of these progenitors can contribute to pathologic conditions. The molecular characteristics of renal progenitors have been extensively studied, revealing that numerous classical and evolutionarily conserved pathways, such as Notch or Wnt/β-catenin, play a major role in cell regulation. Others, such as retinoic acid, renin-angiotensin-aldosterone system, TLR2 (Toll-Like Receptor 2) and leptin, are also important in this process. In this review, we summarize the plethora of molecular mechanisms directing renal progenitor responses during homeostasis and following kidney injury. Finally, we will explore how single cell RNA sequencing could bring the characterization of renal progenitors to the next level, while knowing their molecular signature is gaining relevance in the clinic.

Aquaporin-3 (AQP3) is one of the aquaglyceroporins, which is expressed in the basolateral layer of the skin membrane. Studies have reported that human skin squamous cell carcinoma overexpresses AQP3 and inhibition of its function may alleviate skin tumorigenesis. In the present study, we have applied a virtual screening method that encompasses filters for physicochemical properties and molecular docking to select potential hit compounds that bind to the Aquaporin-3 protein. Based on molecular docking results, the top 20 hit compounds were analyzed for stability in the binding pocket using unconstrained molecular dynamics simulations and further evaluated for binding free energy. Furthermore, examined the ligand-unbinding pathway of the inhibitor from its bound form to explore possible routes for inhibitor approach to the ligand-binding site. With a good docking score, stability in the binding pocket, and free energy of binding, these hit compounds can be developed as Aquaporin-3 inhibitors in the near future.

For condensed systems, the incorporation of quantum chemical solvent effects into molecular dynamics simulations has been a major concern. To this end, quantum mechanical/molecular mechanical (QM/MM) techniques are popular and powerful options to treat gigantic systems. However, they cannot be directly applied because of temporal and spatial discontinuity problems. To overcome these problems, in a previous study, we proposed a corrective QM/MM method, size-consistent multipartitioning (SCMP) QM/MM, and successfully demonstrated that, using SCMP, it is possible to perform stable molecular dynamics simulations by effectively taking into account solvent quantum chemical effects. The SCMP method is characterized by two original features: size-consistency of a QM region among all QM/MM partitioning and partitioning update. However, in our previous study, the performance was not fully elicited compared to the theoretical upper bound, and the optimal partitioning update protocol and parameters were not fully verified. To elicit the potential performance, in the present study, we simplified the theoretical framework and modified the partitioning protocol.

The monkeypox virus (MPXV) has become a major threat due to the increasing global caseload and the ongoing multi-country outbreak in non-endemic territories. Due to limited research in this avenue and the lack of intervention strategies, the present study was aimed to virtually screen bioactive phytochemicals against envelope proteins of MPXV via rigorous computational approaches. Molecular docking and molecular dynamic (MD) simulations were used to investigate the binding affinity of 12 phytochemicals against three envelope proteins of MPXV, viz., D13, A26, and H3. Silibinin, oleanolic acid, and ursolic acid were computationally identified as potential phytochemicals that showed strong binding affinity towards all the tested structural proteins of MPXV through molecular docking. The stability of the docked complexes was also confirmed by MD simulations. ADME analysis also computationally confirmed the drug-like properties of the phytochemicals, thereby asserting their suitability for consumption. Hence, this study envisions the candidature of bioactive phytochemicals as promising inhibitors against the MPXV, serving as template molecules that could further be experimentally evaluated for their efficacy against monkeypox.

Zika virus (ZIKV) has been characterized as one of the potential pathogens and placed under future epidemic outbreaks by the WHO. However, lack of potential therapeutics can result in uncontrolled pandemic like other human pandemic viruses; therefore, prioritized effective therapeutics development has been recommended against ZIKV. In this context, the present study adopted the strategy to explore the lead compounds from Azadirachta indica against ZIKV via concurrent inhibition of the ZIKVpro and ZIKVRdRp proteins using molecular simulations. Initially, structure-based virtual screening of 44 bioflavonoids reported in Azadirachta indica against the crystal structures of targeted ZIKV proteins resulted in the identification of top four common bioflavonoids, viz. rutin, nicotiflorin, isoquercitrin, and hyperoside. These compounds showed substantial docking energy (-7.9 to -11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKVpro (His51, Asp74, and Ser135) and ZIKVRdRp (Asp540, Ile799, and Asp665) by comparison to the reference compounds, O7N inhibitor (ZIKVpro) and Sofosbuvir inhibitor (ZIKVRdRp). Long interval molecular dynamics simulation (500 ns) on the selected docked poses reveals the stability of respective docked complexes contributed by intermolecular hydrogen bonds and hydrophobic interactions. The predicted complex stability was further supported by calculated end-point binding free energy using molecular mechanics generalized born surface area (MM/GBSA) method. Consequently, the identified common bioflavonoids are recommended as promising therapeutic inhibitors of ZIKVpro and ZIKVRdRp for further experimental assessment.

An important stage in SARS-CoV-2 life cycle is the fusion of spike(S) protein with the ACE2 host-cell receptor. Therefore, to explore conserved features in S protein dynamics and to identify potentially novel regions for drugging, we measured variability derived from 791 viral genomes and studied its properties by MD simulation. The findings indicated that S2 subunit (HR1, CH, and CD domains) showed low variability, low fluctuations in MD, and displayed a trimer cavity. By contrast, the RBD domain, which is typically targeted in drug discovery programmes, exhibits more sequence variability and flexibility. Interpretations from MD suggest that the monomer is in constant motion showing transitions up-to-down state, and the trimer cavity may function as a 'bouncing spring' that may facilitates S protein interactions with ACE2. Feasibility of trimer cavity for potential drug target was examined by SBVS screening. Several hits that have already been validated or suggested to inhibit the SARS-CoV-2 virus in cell systems were identified; in particular, the data suggest an action mechanism for such molecules including Chitosan and macrolide types. These findings identify a novel binding-site formed by the S protein, that might assist in future drug discovery programmes aimed at targeting the CoV family of viruses.

The SARS-CoV-2 was confirmed to cause the regional outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China. The 3C-like protease (3CL^pro), an essential enzyme for viral replication, is a valid target to compacts SARS-CoV and MERS-CoV. In this research, an integrated library consisting of 1000 compounds from Asinex Focused Covalent (AFCL) library and 16 FDA-approved protease inhibitors were screened against SARS-CoV-2 3CL^pro. Top compounds with significant docking scores and making stable interactions with catalytic dyad residues were obtained. The screening results in identification of compound 621 from AFCL library as well as Paritaprevir and Simeprevir from FDA-approved protease inhibitors as potential inhibitors of SARS-CoV-2 3CL^pro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CL^pro were characterized using 50 nanoseconds (ns) molecular dynamic (MD) simulation approach. The identified compounds are potential inhibitors worthy of further development as SARS-CoV-2 3CLpro inhibitors/drugs. Importantly, the identified FDA-approved therapeutics could be ready for clinical trials to treat infected patients and help to curb the COVID-19.

The antioxidant activity of molecules constitutes an important factor for the regulation of redox homeostasis and reduction of oxidative stress. Cells affected by oxidative stress can undergo genetic alteration, causing structural changes and promoting the onset of chronic diseases, such as cancer. The in silico study performed here was developed to evaluate the antioxidant potential of two molecules, ZINC08706191 (Z91) and ZINC08992920 (Z20), with recognized epithelial anticancer potential. Molecular docking, chemical-quantum calculations and Pearson's correlation were performed. The Z91 and Z20 molecules showed lower binding free energy (ΔG) values for the receptor-ligand interaction than the reference molecules (caffeine – CAF and ascorbic acid – AA), and better results for values of molecular descriptors correlated with ΔG, resulting in a decrease of ΔG. Strong correlations were observed between ΔG values for the five receptors evaluated and ΔG values of the potential epithelial anticancer activity available in literature. These results attest to the significant antioxidant potential of the Z91 and Z20 molecules and their strong relation with the potential epithelial anticancer activity and may be indicated for further analysis in relation to the control of oxidative stress and epithelial anticancer activity.

Borneol and menthol were two terpenes wildly used as penetrate enhancer in transdermal drug delivery. To explore their penetration enhancement effect towards hydrophilic drug, 5-FU was selected as model drug. A method combined vitro permeation studies and coarse grain molecular dynamics was used to investigate their penetration enhancement effect towards 5-FU. As a result, although both borneol and menthol showed a penetration enhancement effect towards 5-FU, they differed a lot in the penetration enhancement mechanism, which was also thought to account for their different penetration enhancement effect. As for menthol, SC bilayer disrupting effect seemed to be its main mechanism. While for borneol, its mechanism seemed to be more complicated. Except for disrupting the SC bilayer, it could also increase the permeation of 5-FU by enhancing the diffusion rate of 5-FU or inducing the formation of transient pore. All of this enable us a molecular understanding of borneol and menthol’s penetration enhancement effect towards hydrophilic drug, which might provide some guidance in the latter research and application.

Interferons were the original prototype cytokine system discovered in 20th-century research. As the name implies, they were originally thought to be synthesised and secreted between cells. Thanks to technological advances, the processes involved in protein secretion can be explained comparatively more clearly at both the genetic and biochemical levels. The discovery of interferon (IFN) occurred when genetic research was still in its infancy. Franklin and Wilkins discovered the structure and function of deoxyribonucleic acid (DNA) at the same time as Crick and Watson; however, Isaacs and Lindemann, two scientists, described the first IFN in 1957. Mutations can be caused by inherent genetic protein synthesis and during infection as well as within IFN regulation pathways affecting cell proliferation. This remains central to host cell IFN synthesis and effects through IFN protein receptor subunits defined by 6 protein domains. Type II IFN is key to immune cell function secreted by a variety of immune cells, mainly natural killer (NK) as well as T cells. Single–stranded and/or double–stranded RNA/DNA viruses, as well as bacterial infections (e.g., Escherichia coli) and fungal infections (e.g., Aspergillus), also affect IFN regulation. Pathogenic proteins utilise intra/extracellular proteins that sense foreign antigens like Toll–like Receptors (TLRs), affected by mutations within the human cellular IFN transduction pathways. Since the discovery of the third IFN type in 2003, when immune cell phenotypes were further characterised, questions remain about the immunological mechanisms contributing to the regulation of the innate and adaptive host immune system. Alterations in the synthesis of type I/II/III host IFNs can differentially and beneficially alter homeostatic cellular pathways in pathological disease, with type I IFN being synthesised in cancer as well as by homeostatic cells. Therefore, considered here are the overall IFN molecular, cell regulatory mechanisms in the context of immune cell research developments.

A self-consistent charge density-functional tight-binding method combined with molecular dynamics simulations is employed to reveal the effect of polymorph on the thermal decomposition stability of 1,1-Diamino-2,2-Dinitroethylene (FOX-7). Two types of heating, constant temperature heating and temperature-programmed heating, are adopted. Potential evolution indicates that γ-FOX-7 possesses the lowest thermal stability, as it is closer to the decomposition state. Crystal form has an important influence on the thermal decomposition of FOX-7, resulting in different decomposition rates and initial reactions. In general, β- and γ-FOX-7 always decompose more completely than α-FOX-7. This work emphases the importance of polymorph dependent initial decay of an energetic polymorphic compound once heated in a volume constrained condition.

CoFe2O4 is a promissing catalytic material for many chemical reactions. We have used ab initio molecular dynamic simulations to study the structure and reactivity of the A- and B-terminations of the low index CoFe2O4 (001) surfaces to water adsorption at room temperature. Upon adsorption, water partly dissociates on both termination with a higher dissociation degree on the A- termination (30% versus 19%). The 2-fold coordinated Fe3+(tet) in the tetrahedral voids and the 5-fold coordinated Fe3+(oct) in the octahedral voids are the main active sites for water dissociation on the A- and B-termination, respectively. Molecular water, hydroxydes and surface OH resulting from proton transfer to surface oxygens are present on the surfaces. Both water free sur- face terminations undergo reconstruction. The outermost Fe3+(tet) on the A-termination and B-termination move towards the nearby unoccupied octahedral voids. In the presence of a thin film of 32 water molecules, the reconstructions are partially and completely lifted on the A- and B-termination, respectively.

We research the interaction between six representative carbon-based nanoparticles (CBNs) and 20 standard amino acids through all-atom molecular dynamics simulations. The six carbon-based nanoparticles are fullerene(C60), CNT55L3, CNT1010L3, CNT1515L3, CNT2020L3, and two-dimensional-graphene(Graphene33). Their curvatures decrease sequentially, and all of CNT are single-walled carbon nanotubes. We have observed that as the curvature of CBNs decreases, the adsorption effect of 20 amino acids with them has an increasing trend. In addition, we also used multi-dimensional clustering to analyze the adsorption effects of 20 amino acids on six carbon-based nanoparticles. We observed that the π-π interaction still plays an extremely important role in the adsorption of amino acids on carbon-based nanoparticles. Individual long-chain amino acids and “Benzene-like” Pro also have a strong adsorption effect with carbon-based nanoparticles.

Drug discovery has been initially attributed to coincidence or trial and error where the traditional approach was complex, lengthy, and expensive. Conventional drug discovery methods require the costly random screening of synthesized compounds or natural products. Another downside for this approach is the wide dependency on the experimental use of animals for in vi-vo testing. Currently, in silico modeling has become a vital tool for drug discovery and repurposing, and molecular docking is being used to find the best matching between a ligand and a molecule. Practical application of in silico docking will predict the biomolecular interactions between the drug and the target host. Beauvericin (BEA) is an emerging mycotoxin produced by the entomopathogenic fungus Beauveria bassiana. Originally investigated for its pesticide capability, BEA is now considered as a molecule of interest for its potentially diverse biotechnological applications in the pharmacological industry and the field of medicine. In this manuscript, we will provide an overview of the repurposing of BEA into a potentially superior therapeutic molecule in a broad range of diseases. Furthermore, considerable attention has been given to the fundamental role of in silico techniques to i) further investigate the spectrum of this secondary metabolite and ii) elucidate the pathways of BEA for its promising therapeutic action

Bioluminescence – i.e., the emission of visible light by living organisms - is defined as a biochemical reaction involving, at least, a luciferin substrate, an oxygen derivative, and a specialised luciferase enzyme. In some cases, the enzyme and the substrate are durably associated and form a photoprotein. While this terminology is educatively useful to explain bioluminescence, it gives a false idea that all luminous organisms are using identical or homologous molecular tools to achieve light emission. As usually observed in biology, reality is more complex. To date, 11 different luciferins have indeed been discovered, and several non-homologous luciferases lato sensu have been identified which, all together, confirms that bioluminescence emerged independently multiple times during the evolution of living organisms. While some phylogenetically related organisms may use non-homologous luciferases (e.g., at least four convergent luciferases are found in Pancrustacea), it has also been observed that phylogenetically distant organisms may use homologous luciferases (e.g., parallel evolution observed in some cnidarians, tunicates and echinoderms that are sharing a homologous luciferase-based system). The evolution of luciferases then appears puzzling. The present review takes stock of the diversity of known “bioluminescent proteins”, their evolution and potential evolutionary origins. A total of 134 luciferase and photoprotein sequences have been investigated (from 75 species and 11 phyla), and our analyses identified 12 distinct types – defined as a group of homologous bioluminescent proteins. The literature review indicated that genes coding for luciferases and photoproteins have potentially emerged as new genes or have been co-opted from ancestral non-luciferase/photoprotein genes. In this latter case, the homologous gene’s co-options may occur independently in phylogenetically distant organisms.

Li₂MnO₃ is critical component in the well-studied Li-excess cathode materials xLi₂MnO₃•(1- x)LiMO₂ for achieving high lithium storage capacity. In this article, the diffusion of Li ions in Li₂MnO₃ is studied using molecular dynamics (MD) simulation with well-behaved empirical force fields obtained by fitting against the crystal structure from experiment and phonons calculated using Density Function Theory (DFT). We have found two possible tetrahedral hopping channels, 0-TM and 1-TM(Mn⁴⁺) channel, which are differentiated by the face sharing octahedral cations. Simulation results show that the 0-TM channel is active for Li hopping, while 1-TM(Mn4+) channel is inactive. During the delithiation process, the Li ions in the TM layered are firstly removed, then those in the Li layer. However, the Li ions will be trapped in the tetrahedral 0-TM channels as long as the four face sharing octahedral sites are cleared. Up to x=1.0 for Li₂-xMnO₃, almost all the Li ions are located at the tetrahedral sites, forming a regular array along a axis. The de-intercalation of tetrahedral Li ions requires a high voltage (>5.2 V vs. Li/Li+), limiting the practical capacities measured in lab. The diffusion of Mn ions into the Li layers is observed in a deeper delithiated structure (x=1.2 for Li₂-xMnO₃), indicating an initial phase transformation to a spinel-like structure. However, the Mn ions are mainly trapped in the tetrahedral sites in the Li layer, instead of the octahedral sites fin spinel-like structure. A few of Mn ions diffusing into the octahedral sites in Li layers have no face sharing tetrahedral Li ions, revealing a further Li de-intercalation is imperative for the complete phase transformation. Our model is not stable for x≥1.4 in Li₂-xMnO₃. Other charge compensation mechanism should be considered in this high delithiation stage, eg. oxygen release.

Introduction of exotic species in new areas through anthropic action is one of the major problems that can affect biodiversity. Branchiomma luctuosum is known for its highly invasive potential and the actual occurrence of species commonly associated with port activity areas is an extra evidence that this anthropogenic activity should not be underestimated. In order to develop suitable molecular markers for future studies on colonization routes and population dynamics of the invading individuals of B. luctuosum, nine highly polymorphic microsatellite loci were isolated and their polymorphism levels were evaluated. These loci showed a range of number of alleles per locus from five to ten and all loci had a high level of genetic diversity, and exhibited significant heterozygote deficiencies probably due to the presence of null alleles. Significant deviations from the Hardy-Weinberg equilibrium were detected at several loci and most of them were related to a heterozygous deficit. Heterozygous deficiency can be expected in this case due to the biology and history of this invasive species, in relation to its recent introduction in Brazilian coast and possible action of multiple introductory events.

Tuberculosis (TB) continues to pose a global health challenge, exacerbated by the rise of drug-resistant strains. The development of new TB therapies is an arduous and time-consuming process. To expedite the discovery of effective treatments, computational structure-based drug re-purposing has emerged as a promising strategy. From this perspective, conditionally essential targets present a valuable opportunity, and the mycobactin biosynthesis pathway stands out as a prime example highlighting the intricate response of Mycobacterium tuberculosis (Mtb) to changes in iron availability. This study focuses on the re-purposing and revival of FDA-approved drugs (library) as potential inhibitors of MbtA, a crucial enzyme in mycobactin biosynthesis in Mtb conserved among all species of mycobacteria. Literature suggests this pathway to be associated with drug efflux pumps, which potentially contribute to drug resistance. This makes it a potential target for antitubercular drug discovery. Herein we utilized cheminformatics and structure-based drug repurposing approaches, viz., molecular docking, dynamics, and PCA analysis, to decode the intermolecular interactions and binding affinity of the FDA-reported molecules against MbtA. The virtual screening revealed ten molecules with significant binding affinities and interactions with MbtA. These drugs, originally designed for different therapeutic indications (4: antiviral, 3: anticancer, 1: CYP450 inhibitor, 1: ACE inhibitor, and 1: leukotriene antagonist), are repurposed as potential MbtA inhibitors. Furthermore, our study explores the binding modes and interactions between these drugs and MbtA, shedding light on the structural basis of their inhibitory potential. Principal component analysis highlighted significant motions in MbtA-bound ligands, emphasizing the stability of the top Protein-Ligand Complexes (PLCs). This computational approach provides a swift and cost-effective method for identifying new MbtA inhibitors, which can subsequently undergo validation through experimental assays. This streamlined process is facilitated by the fact that these compounds are already FDA-approved and have established safety and efficacy profiles. This study has the potential to lay the groundwork for addressing the urgent global health challenge at hand, specifically in the context of combating Antimicrobial Resistance (AMR) and Tuberculosis (TB).

Polo-like kinase 1 (PLK1) plays a pivotal role in cell division regulation and emerges as a promising therapeutic target for cancer treatment. Consequently, the development of small-molecule inhibitors targeting PLK1 has become a focal point in contemporary research. The adenosine triphosphate (ATP)-binding site and the polo-box domain in PLK1 present crucial interaction sites for these inhibitors, aiming to disrupt the protein's function. However, designing potent and selective small-molecule inhibitors can be challenging, requiring a deep understanding of protein-ligand interaction mechanisms at these binding sites. In this context, our study leverages the fragment molecular orbital (FMO) method to explore these site-specific interactions in-depth. Through the FMO approach, we used the FMO method to elucidate the molecular mechanisms of small-molecule drug binding to these sites to design PLK1 inhibitors that are both potent and selective. Our investigation further entailed a comparative analysis of various PLK1 inhibitors, each characterized by distinct structural attributes. This comparison enhanced our understanding of the structure-activity relationships of these inhibitors, underscoring the efficacy of the FMO method in identifying critical binding features and predicting binding modes for small-molecule ligands. Furthermore, Our research spotlighted "hot spot" residues instrumental for selective and robust PLK1 binding. Our findings offer profound insights, priming the rational design of innovative potential PLK1 inhibitors with significant implications for developing anticancer therapeutics.

In this study, we investigate the structural changes, electronic properties, and charge redistribution within azo-bithiophene (Azo-BT) chemisorbed monolayers under different light stimuli using density functional theory and molecular dynamics simulations. We consider two types of switches, Azo-BT and BT-Azo, with different arrangements of the Azo and BT blocks counting from the anchor thiol group. The chemisorbed monolayers of pure cis- and trans-isomers with a surface concentration of approximately 2.7 molecules per nm2 are modeled on a gold surface using classical all-atom molecular dynamics. Our results reveal significant shrinkage of the BT-Azo layer under UV illumination, whereas the thicknesses of the Azo-BT layer remain comparable for both isomers. This difference in behavior is attributed to the ordering of the trans-molecules in the layers, which is more pronounced for Azo-BT, leading to a narrow distribution of the inclination angle to the gold surface. Conversely, both layers consisting of cis-switches exhibit disorder, resulting in similar brush heights. To study charge transfer within the immobilized layers, we analyze each snapshot of the layer and calculate mean charge transfer integrals using Nelsen’s algorithm for a number of interacting neighboring molecules. Combining these integrals with reorganization energies defined for the isolated molecules, we evaluate the charge transfer rates and mobilities for electron and hole hopping within the layers at room temperature based on Marcus’ theory. This research offers new perspectives for the innovative design of electrode surface modifications and provides insights into controlling charge transfer within immobilized layers using light triggers. Additionally, we identify molecular properties that are enhanced through specific molecular design, which contributes to the development of more efficient molecular switches for various electronic applications.

Infection of hosts by morbilliviruses is facilitated by the interaction between viral hemagglutinin (H-protein) and the signaling lymphocytic activation molecule (SLAM). Recently, the functional importance of the N-terminal region of human SLAM as a measles virus receptor was demonstrated. However, the functional roles of this region in the infection process by other morbilliviruses and host range determination remain unknown partly because this region is highly flexible, which has hampered accurate structure determination of this region by X-ray crystallography. In this study, we analyzed the interaction between the H-protein from canine distemper virus (CDV-H) and SLAMs by a computational chemistry approach. Molecular dynamics simulations and fragment molecular orbital analysis demonstrated that the unique His28 in the N-terminal region of SLAM from Macaca is a key determinant that enables formation of a stable interaction with CDV-H, providing a basis for CDV infection in Macaca. The computational chemistry approach presented should enable determination of molecular interactions involving regions of proteins that are difficult to predict from crystal structures because of their high flexibility.

Three-dimensional structure of six closely related hydrogenases from purple bacteria has been modeled by combining template-based and ab initio modeling approach. The results lead to conclusion that there should be 4Fe3S-cluster in the structure of these enzymes. Thus, these hydrogenases could drive attention for exploring their oxygen tolerance and practical applicability in hydrogen fuel cells. Analysis of 4Fe3S-cluster's microenvironment showed intragroup heterogeneity. Possible function of the C-terminal part of the small subunit in membrane binding has been discussed. Comparison of the built models with existing hydrogenases of the same subgroup (membrane-bound oxygen-tolerant hydrogenases) has been carried out. Analysis of intramolecular interactions in the large subunits showed statistically reliable differences in number of hydrophobic interactions and number of ionic interactions. Molecular tunnels were mapped in the models and compared with structures from PDB. Protein-protein docking showed that these enzymes could exchange electrons in oligomeric state, which is important for oxygen-tolerant hydrogenases. Molecular docking with model electrode compounds showed mostly the same results as with hydrogenases from E.coli, H. marinus, R. eutropha, S. enterica; some interesting results were shown in case of HupSL from Rba. sphaeroides and Rvx. gelatinosus.

Dysregulation of the arsenal of cells, growth factors, cytokines, proteases, and proteins involved in wound healing (WH), could delay the healing process. Plants and plant-derived molecules (PDMs) have been used as medicines for skin wounds. This study aimed to select and evaluate the pro-healing capacity of PMDs. Thirty-three PDMs and 10 therapeutic targets (TTs) were chosen for molecular docking and PDMs: aristolochic acid (AA), α-copaene, selinenes, β-caryophyllene (BC), and BCoxide, and TTs: metalloproteinase (MMP) 3, MMP13, and tumor necrosis factor (TNF α) for molecular dynamics. The bests inhibitor was AA, but because of its toxicity, BC and BCoxide were chosen for evaluation in HaCat cells and BALB/c mice excisional model. Both compounds were not toxic, and higher percentages of lesion area closure (LAC) were induced by BC treatment (p<0.05). All mice healed; however, an initial delay of LAC was induced by 0.05, 0.1% BCoxide, 0.1% BC, and allantoin. At the end of treatment, lower numbers of mast cells, level of cellular infiltrates (except 1% BCoxide and 0.05, 0.5%BC), epidermal thickness tendency (except 0.1, 0.5% BCoxide), and higher values of SC-thickness, and collagen fibers only by 0.5% BC treatment compared with untreated control (p<0.05) were observed. Our results show that BC is a promising multitarget candidate for wound healing treatment and optimization campaigns.

Most existing cancer therapies negatively affect normal tissue as well as cancerous tissue. A potentially effective strategy for treating cancer that precludes off-target damage and could be an option for most patients would involve targeting one or more mutations that are ubiquitous in the given patient’s tumor(s). To effect this strategy, one would employ multi-region sequencing of a patient’s primary tumor and metastases to seek out mutations that are shared between all or at least most regions. Once the target or targets are known, one would ideally rapidly generate a molecular switch for at least one of said ubiquitous mutations that can distinguish the mutated DNA, RNA, or protein from the wild-type version and subsequently trigger a therapeutic response. I propose that the therapeutic response involve the replication of an oncolytic virus or intracellular bacterium, as any mutation can theoretically be detected by a vector that enters the cell - and automatic propagation could be very helpful. Moreover, the mutation “signal” can be easily enhanced through transcriptional and translational (if the target is an intracellular protein) enhancement. Importantly, RNA may make the best target for the molecular switches in terms of amplification of the signal and ease of targeting.

Thrombosis has threatened human health in past decades. Bacillus nattokinase is a potential thrombolytic drug without side-effect and low cost and has been introduced into the consumer market as a functional food or dietary supplement. This review firstly summarizes the biodiversity sources and fermentation process of nattokinase, and systematically expounds the structure, cata-lytic mechanism and enzymatic properties of nattokinase; In view of the problems of low fermen-tation yield, insufficient activity and stability of nattokinase, this review discusses the heterologous expression of nattokinase in different microbial hosts, and summarizes the protein and genetic en-gineering progress of nattokinase-producing strains; Finally, this review summarizes the clinical application of nattokinase.

The past two decades have witnessed the introduction of and then a steady increase in the use of computational techniques in the study and development of molecularly imprinted polymers (MIPs). Molecular dynamics (MD) based studies have had a significant role in this development as they can provide insights concerning the mechanisms governing the molecular level events underlying MIP synthesis and MIP-ligand interactions and can be used for the identification of preferred monomer compositions and for the prediction of MIP properties. We here review the role that MD has played in the development of molecular imprinting and examine the different types of MD strategies that have been used, including their advantages and challenges. Recent trends in the application of MD to the study of MIPs are presented, along with a perspective on the future importance of MD-based studies for the development of molecular imprinting science and technology.

This research aims to find out whether the synthetic 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with Candida albicans. Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a We are interested in using molecular docking and molecular dynamics modelling to investigate the interaction between the derivatives of 1, 2, 4-triazine and the resulting lanosterol 14 - demethylase (CYP51) of Candida albicans The inhibition of Candida albicans CYP51 is the main goal of our research. The 1, 2, 4-triazine and its derivatives have been docked to the CYP51 enzyme, which is involved in Candida albicans Multidrug Drug Resistance (MDR). Autodock tools were used to identifying the binding affinities of molecules against the target proteins. Compared to conventional fluconazole, the molecular docking results indicated that each drug has a high binding affinity for CYP51 proteins and forms unbound interactions and hydrogen bonds with their active residues and surrounding allosteric residues. The docking contacts were made using a 10 ns MD simulation with nine molecules. RMSD, RMSF, hydrogen bonds, and the Rg all confirm these conclusions. In addition, these compounds were expected to have a favorable pharmacological profile and low toxicity. The compounds are being offered as scaffolds for the development of new antifungal drugs and as candidates for future in vitro testing.

This review presents an updated overview of research concerning Leishmania protein structures, primarily sourced from the Protein Data Bank (PDB), that play a role in the metabolic pathways of the Leishmania parasite. Furthermore, we assess the current progress in the identification and development of bioactive chemical agents aimed at addressing this substantially overlooked tropical disease. We have analyzed experimental data obtained from in vitro, in vivo and in silico sources. This data has been categorized into four main areas: a) vector taxonomy and geographic distribution; b) parasite taxonomy and geographic distribution; c) enzymatic functions of proteins engaged in parasite/host interactions throughout various developmental stages (such as oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, and cytokines); and d) established and experimental treatments employing bioactive chemical compounds. Our objective is to establish a foundational point of reference for research efforts concentrating on the elucidation of interaction mechanisms and the processes of ligand-protein activation/inactivation, specifically linked to Leishmania infections. Consequently, we emphasize enzymes recognized for their involvement in the biochemical pathways incited during Leishmania infection episodes. This review encapsulates the current understanding, offering insights to inform and direct future explorations aimed at targeting proteins and pathways to enhance the management of Leishmania-related diseases.

This study investigates the impact of temperature-induced quantum proton tunneling probability on DNA amplification during polymerase chain reactions (PCR). Using a simulation model based on a Gaussian wavefunction and finite-difference time-domain method, quantum tunneling of protons across square potential barriers is examined. The results unveil consistent probability distributions for quantum tunneling across various PCR temperatures, with distinct oscillation patterns emerging post-barrier crossing. Acknowledging limitations in initial conditions due to temperature-dependent proton energy, the study highlights the need for refined models and experimental validation. These findings accentuate the potential interplay between quantum mechanics and biological systems, prompting further research to understand quantum tunnelling’s comprehensive effect on genetic variations and molecular processes.

Ebola virus is a zoonotic virus comprised of 6 different species designated within the family Filoviridae and genus Ebolavirus. The first recorded outbreak of an Ebola virus (EBOV) was in Yambuku, Zaire (ZEBOV) in 1976, followed by Sudan Ebola virus (SUBOV) later that year. Outbreaks have been increasing throughout the 21st century, and mortality rates can reach up to 90%. Such extraordinary virulence is evidenced with few pathogens, similarly with Marburg virus (MARV) that originated in Uganda and was first detected in Germany in 1967. The virulent nature of filovirus disease has established these related viruses as a formidable global concern. There are currently four types of Ebolaviridae species known to infect humans, with two more recently identified in other animals that are genomically different with respect to cellular pathogenesis or aetiology of disease. Recent advances into understanding the pathogenesis of filovirus disease infections have been remarkable, yet the immunological response to filovirus infection remains unknown. Scientific analysis of cellular mechanisms can provide insight into virulence factors utilised by other pathogenic viruses that also cause febrile illness with occasional haemorrhagic fever in humans. In this review, we aim to provide a brief summary of EBOV proteins and the role of innate and adaptive immune cells known since 2000. We will consider the relevance and implications of immunological proteins measured by CD marker, alongside cytokine, chemokine and other biologically relevant pathways, as well as genetic research. Thorough understanding of immunological correlates affecting host responses to Ebola viruses will facilitate both clinical and applied research knowledge, contributing towards protection against potential public health threats.

Zirconium nitride (Zr-N) is a candidate material for inert matric fuel elements in breeder reactors. They have shown exceptional resistance to radiative corrosive environments. They have shown excellent resistance to radiation stability at operational conditions in current generation reactors. But being a candidate nuclear fuel material in generation reactors, their radiation stability at higher temperature conditions observed has not been reported. We have employed molecular dynamics simulations to study the damage cascades and radiation stability of ZrN at 600K. The process of primary damage evolution by considering varying overlapping cascades with 10, 20 keV incident PKA’s reported here. The defects interface interaction and diffusion mechanism at the interface are reported.

The analysis of high-temperature physicochemical properties of theK₃AlF₆-Na₃AlF₆-AlF₃ molten salt system is crucial for practical production of electrolytic aluminum. In this paper, the physicochemical properties of the K₃AlF₆-Na₃AlF₆-AlF₃ molten salt electrolyte system at 1173 K and standard atmospheric pressure were simulated using molecular dynamics calculations. The effects of Zr、B、C、W、Ti、Hf、Nb、and Ta on the radial distribution function, coordination number, viscosity and conductivity of the electrolyte system are discussed in detail. The simulation results show that the coordination number between Al-F and the conductivity is decreasing as the content of B²- increases. And the coordination number between Al-F and the viscosity is decreasing as the content of Zr⁴⁺ increases. With the addition of impurity elements such as C, W, Ti, Hf, Nb, and Ta, the data show that C has no significant effect on this electrolyte system, while the presence of W will decrease the coordination number between Al-F in the system. The presence of Ti, Hf, Nb, and Ta may intensify the decomposition reaction between one of the Al-F ligands, which increases the coordination number between Al-F and the number of ions in the electrolyte. This work provides theoretical support for the subsequent study of inert anodes containing Zr, B, Ti, Hf, Nb, and Ta.

Background: Strongyloidiasis, a neglected disease caused by intestinal nematodes of the genus Strongyloides, is endemic to tropical and subtropical areas such as Vietnam. The morphological diagnosis of larvae by Hara Mori culture technique and microscopicare are considered the standard diagnostic procedures in the endemic areas of Strongyloides spp. However, they could only identify the genus, not the species of Strongyloides. DNA-molecular techniques which are highly sensitive and more cost-effective have been increasingly utilized in detection of Strongyloides species. This study aims to determine prevalence and the species of Strongyloides among resident population in Duc Hoa district, Long An province, Southern Vietnam. Methods: A cross-sectional study was conducted using 1,190 stool samples collected in Duc Hoa district, Long An province, Vietnam, from July, 2017 to November 2018. The stool specimens were transported to the Laboratory of Medical Parasitology, Pham Ngoc Thach University of Medicine within two hours of collection at an appropriate temperature of 25 oC. All samples were stored at 2 - 8°C and processed within 48 hours for microscopic examination. Molecular detection was carried out at Laboratory of Molecular Biology, Pham Ngoc Thach University of Medicine, Hochiminh city, VietNam. Results: Of the 1,190 samples tested, Strongyloides spp. larvae were detected in 79 specimens (6.6%) by two classical parasitological methods, namely direct microscopy and the modified Harada-Mori filter paper culture. DNA was extracted from 70 of the 79 samples of Strongyloides spp. larvae, which was subsequently characterized by real-time PCR amplification of the 18S and 28S regions of the rDNA gene. The results showed that 97.1% of the DNA samples were S. stercoralis, 2.9% were co-infections with S. ratti and S. stercoralis, and 2.9% belonged to S. ratti. For all 14 isolates, nucleotide sequencing was compared with other human pathogenic species of Strongyloides whose sequences are available in GenBank. The identity of 12/14 sequences were confirmed as S. stercoralis with a high level of similarity (91.3% - 100%) and over 98% for S. ratti. Between the two co-infection samples, the higher similarity belonged to S. stercoralis. Conclusion: A molecular amplification of small subunit ribosome RNA followed by sequence analysis has been proved to be a suitable method for discrimination of Strongyloides spp. retrieved from stool samples.

Leishmaniasis is a neglected tropical disease and affects more than 350 million people worldwide. However, there are no vaccines for humans, and current treatment is hampered due to its high cost, numerous side effects, and painful administration routes. Ending its epidemics by 2030 has become a United Nations goal, and the multitarget drug strategy emerges as a promising alternative. Flavonoids are an example of multitarget compounds and organic synthesis represents a tool to obtain high yields of these molecules. In our study, we synthesized 17 flavonoid analogs using a scalable, easy-to-reproduce, and inexpensive method. All compounds demonstrated an impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y, which are highly expressed in the amastigote stage, the target form of the parasite. Compounds 3c, f12a, and f12b stood out as effective against all isoforms and intermolecular interactions were investigated through a molecular modeling study. The compounds were highly potent against the parasite and demonstrated low cytotoxic action against mammalian cells. The results were pioneering, representing an advance in the investigation of the mechanisms behind the antileishmanial action of flavonoid derivatives. Furthermore, compounds have shown to be promising leads for the design of other cysteine protease inhibitors for the treatment of leishmaniasis diseases.

Wildfires have continued to increase in frequency and severity in Southern California due in part to climate change. To gain a further understanding of microbial soil communities’ response to fire and functions that may enhance post-wildfire resilience, soil fungal and bacterial microbiomes were studied from different wildfire areas in the Gold Creek Preserve within the Angeles National Forest using 16S, FITS, 18S, 12S, PITS, and CO1 amplicon sequencing. Sequencing datasets from December 2020 and June 2021 samplings were analyzed using DNA Subway, ranacapa, stats, vcd, EZBioCloud, and mixomics. Significant differences were found among bacterial and fungal taxa associated with different fire areas in the Gold Creek Preserve. There was evidence of seasonal shifts in the alpha diversity of the bacterial communities. In the sparse partial least squares analysis, there were strong associations (r>0.8) between longitude, elevation, and a defined cluster of Amplicon Sequence Variants (ASVs). The Chi-square test revealed differences in fungi:bacteria (F:B) proportions between different trails (p=2*10^-16). sPLS results focused on a cluster of Green Trail samples with high elevation and longitude. Analysis revealed the cluster included the post-fire pioneer fungi Pyronema, and Tremella. Chlorellales algae, and pathogenic Fusarium sequences were elevated. Bacterivorous Corallococcus, which secretes antimicrobials, and bacterivorous flagellate Spumella, were associated with the cluster. There was functional redundancy in clusters that were differently composed, but shared similar ecological functions. These results implied a set of traits for post fire resiliency. These included photo-autotrophy, mineralization of pyrolyzed organic matter and aromatic/oily compounds, pathogenicity and parasitism, antimicrobials, and N-metabolism.

Our work uses Iterative Boltzmann Inversion (IBI) to study the coarse-grained interaction between 20 amino acids and the representative carbon nanotube CNT55L3. IBI is a multi-scale simulation method that has attracted the attention of many researchers in recent years. It can effectively modify the coarse-grained model derived from the Potential of Mean Force (PMF). IBI is based on the distribution result obtained by All-Atom molecular dynamics simulation, that is, the target distribution function, the PMF potential energy is extracted, and then the initial potential energy extracted by the PMF is used to perform simulation iterations using IBI. Our research results have gone through more than 100 iterations, and finally, the distribution obtained by coarse-grained molecular simulation (CGMD) can effectively overlap with the results of all-atom molecular dynamics simulation (AAMD). In addition, our work lays the foundation for the study of force fields for the simulation of the coarse-graining of super-large proteins and other important nanoparticles.

Molecular iodine (I2) induces apoptotic, antiangiogenic, and antiproliferative effects in breast cancer cells. Little is known about its effects on the tumor immune microenvironment. We studied the effect of oral (5 mg/day) I2 supplementation alone (I2) or together with conventional chemotherapy (Cht+I2) on the im-mune component of breast cancer tumors from a previously published pilot study conducted in Mexico. RNA-seq, I2 and Cht+I2 samples showed significant increases in expression of Th1 and Th17 pathways. Tumor immune composition determined by deconvolution analysis revealed significant increases in M0 macrophages and B lymphocytes in both I2 groups. Real-time RT-PCR showed that I2 tumors overexpress T-BET (p = 0.019) and interferon-gamma (IFNγ; p = 0.020) and silence tumor growth factor-beta (TGFβ; p = 0.049); whereas in Cht+I2 tumors, GATA3 is silenced (p = 0.014). Preliminary methylation analysis shows that I2 activates IFNγ gene promoter (by increasing its unmethylated form) and silences TGFβ in Cht+I2. In conclusion, our data showed that I2 supplements induce the activation of the immune response and that when combined with Cht, the Th1 pathways are stimulated. The molecular mechanisms involved in these responses are being analyzed, but preliminary data suggest that methylation/demethylation mechanisms could also participate.

The main aim of this study is to identify inhibitory binding potent of the available commercially alkaloids, against the crystal structure of acetylcholinesterase (AChE) protein by in silico studies. The inhibitory data of the compounds should be compared with the internal ligand as well as standard AChE inhibitor Aricept (which is used for the treatment of all stages of Alzheimer’s disease). AutoDock 4.0 is used for the docking study, conformational orientation site analysis, and, with the help of docking, we have calculated parameters like binding energy and inhibition constant. Docking's study showed that Glabridin, Isorosmanol, Quercetin, Honokiol, Eckol, Sargaquinoic acid, and Ginsedosides revealed strong binding affinity with the enzyme. Moreover, The ADMET profiling and physicochemical properties of the selected compounds are evaluated using the Molinspiration and Data warrior software. By showing a strong binding affinity value, positive bioactivity score, and good pharmacokinetic properties, the top compound was determined. After evaluation with all parameters, the compound Glabridin and Ginsedosides show the most potent inhibitory effect towards the acetylcholinesterase, so this compound could be used as a novel is required to treat Alzheimer's disease.

introduction: Cancer, as clusters of diseases, uncontrolled cell proliferation due to tumor suppressor genes inactivation, oncogenes activation, and external factors.Methods: To review data, electronic databases such as Nature, PubMed/PMC, Science Direct/Elsevier, EMBASE, and Google Scholar were used.Results: Derestricted forms of proto-oncogenes are oncogenes, which had vital roles in various paths of cell cycle modulation. Translocations and chromosomal rearrangement and/or mutations in genes are the major factors for the transformation of proto-oncogene to oncogenes. Herein, to prevent the proliferation of cancerous cells, oncogenes are targeted molecules. From a cancer therapeutic target point of view, oncogene silencing and deletion, mutation of tumor suppressor genes, and retroviral therapy molecular techniques were developed. Conclusion: To establish a cancer-free world, the most commonly used techniques are: Ribose Nucleic Acid interferences, zinc finger nucleases, and CRISPR.Keywords: Cancer, Oncogenes, Proto-oncogenes, molecular technique

The selectivity in the simultaneous detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA) has been an open problem in the biosensing field. Many surface modification methods were carried out for glassy carbon electrodes (GCE), including the use of graphene oxide and amino acids as a selective layer. In this work, molecular dynamics (MD) simulations were performed to investigate the role of serine oligomers on the selectivity of the AA, DA, UA analytes. Our models consisted of a graphene oxide (GO) sheet under a solvent environment. Serine tetramers were added into the simulation box and were adsorbed on the GO surface. Then, the adsorption of each analyte on the mixed surface was monitored from MD trajectories. It was found that the adsorption of AA was preferred by serine oligomers due to the largest number of hydrogen-bond forming functional groups of AA, while UA was the least preferred due to its highest aromaticity. Finally, the role of hydrogen bonds on the electron transfer selectivity of biosensors was discussed with some previous studies.

The oncogenic potential of high-risk HPVs is focused on producing the E6 and E7 oncoproteins responsible for disrupting the control of the cell cycle. Epidemiological studies propose the presence of the N29S and H51N variants of the HPV16 E7 protein as a significant association with cervical cancer. It has been suggested that changes in the amino acid sequence of E7 variants may affect the oncoprotein 3D structure; however, this remains unknown. Analysis of the structural differences of the HPV16 E7 protein and its variants (N29S and H51N) was performed through homology modeling and structural refinement by molecular dynamics simulation. We propose for the first time a 3D structure of the E7 reference protein and two of its variants (N29S and H51N) and conclude that the mutations induced by the variants in N29S and H51N have a significant influence on the 3D structure of the E7 protein of HPV16, which could be related to the oncogenic capacity of this protein.

Tuberculosis (TB) is a contagious disease, caused by Mycobacterium tuberculosis (MTB) that has infected and killed a lot of people in the past. At present treatments against TB are available at a very low cost. Since these chemical drugs have many adverse effects on health, more attention is now given on the plant-derived phytochemicals as potential agents to fight against TB. In this study, 5 phytochemicals, 4-hydroxybenzaldehyde, benzoic acid, bergapten, psoralen, and p-hydroxybenzoic acid, are selected to test their potentiality, safety, and efficacy against two potential targets, the MTB RNA polymerase and enoyl-acyl carrier protein (ACP) reductase, the InhA protein, using various tools of in silico biology. The molecular docking experiment, drug-likeness property test, ADME/T-test, P450 SOM prediction, pharmacophore mapping, and modeling, solubility testing, DFT calculations, and PASS prediction study had confirmed that all the molecules had the good potentiality to inhibit the two targets. However, two agents, 4-hydroxybenzaldehyde and bergapten were considered as the best agents among the five selected agents and they also showed far better results than the two currently used drugs, that function in these pathways, rifampicin (MTB RNA polymerase) and isoniazid (InhA protein). These two agents can be used effectively to treat tuberculosis.

There has recently been interest in the development of small-molecule inhibitors of the oligomerization of Bacillus anthracis protective antigen for therapeutic use. Some of the proposed lead compounds have, however, unfavorable solubility in aqueous medium, which prevents their clinical use. In this computational work, we have designed several hundreds of derivatives with progressively higher hydrosolubility and tested their ability to dock the relevant binding cavity. The highest-ranking docking hits were then subjected to 125 ns-long simulations to ascertain the stability of the binding modes. Several of the potential candidates performed quite disappointingly , but two molecules showed very stable binding modes throughout the complete simulations. Besides the identification of these two promising leads, these molecular dynamics simulations allowed the discovery of several insights that shall prove useful in the further improvement of these candidate towards higher potency and stability.

Molecular dynamics simulations were carried out to investigate the atomic structure of a model Cu64Zr36 bulk metallic glass (BMG). It is found that the amount of icosahedral content of the system is significantly increased in a well relaxed structure. While we considered four connection types of vertex-, edge-, face-, and volume-sharing, the huge cluster in the relaxed samples mainly involve volume-type connection and exhibits a remarkable athermal plasticity that great stiffness and great yield strength compared to the as-quenched samples. In addition, the bond-angle distribution of annealed sample shows sharp peaks at specific bond angles which is an evidence of crystallized Laves-phase formed by icosahedral atoms, however the peaks are to be broaden after loading, which indicates decreasing amount of icosahedral content and their shape distortion. These results suggest that icosahedral content in a bulk metallic glasses plays a key role to determine the mechanical properties such as rigidity and maximum stress carrying capacity.