Dindi, U.M.R.; Sadiq, S.P.; Al-Ghamdi, S.; Alrudian, N.; Salman, B.D.; Abuderman, A.A.; Mohammad, S.; Ramesh, T.; Vilwanathan, R. In-Silico and In-Vitro Functional Validation of Imidazole Derivatives as Potential Sirtuin Inhibitor. Preprints2023, 2023081350. https://doi.org/10.20944/preprints202308.1350.v1
APA Style
Dindi, U.M.R., Sadiq, S.P., Al-Ghamdi, S., Alrudian, N., Salman, B.D., Abuderman, A.A., Mohammad, S., Ramesh, T., & Vilwanathan, R. (2023). In-Silico and In-Vitro Functional Validation of Imidazole Derivatives as Potential Sirtuin Inhibitor. Preprints. https://doi.org/10.20944/preprints202308.1350.v1
Chicago/Turabian Style
Dindi, U.M.R., Thiyagarajan Ramesh and Ravikumar Vilwanathan. 2023 "In-Silico and In-Vitro Functional Validation of Imidazole Derivatives as Potential Sirtuin Inhibitor" Preprints. https://doi.org/10.20944/preprints202308.1350.v1
Abstract
Sirtuins are a family of Class III epigenetic modifying enzymes involved in regulating cellular processes through the removal of acetyl groups from proteins. They rely on NAD+ as a coenzyme in contrast with classical HDACs (Class I, II, and IV) that depends on Zn+ for their activation, linking their function to cellular energy levels. There are seven mammalian sirtuin isoforms (SIRT1-7), each located in different subcellular compartments. Sirtuins act as master regulators of cellular homeostasis, responding to changes in nutrient availability and energy status. They play vital roles in diverse physiological and pathological conditions, making them promising therapeutic targets for various diseases, including cancer, neurodegenerative disorders, and metabolic diseases. High levels of SIRT6 are involved in the cancer progression of many tumor types and our previous studies revealed that sirtuin 6 was highly expressed in NSCLC cells and its inhibition potentially favored apoptosis and cell cycle arrest. Sirt6 emerged as a promising target and inhibitors of natural and synthetic sources are highly warranted. Imidazole derivatives are often investigated as sirtuin regulators due to their ability to interact with the binding site and modulate their activity. Imidazole bestows many possible substitutions on its ring and neighboring atoms, to design and synthesize derivatives with specific target selectivity and improved pharmacokinetic properties, optimizing drug development. We recently developed imidazole-based derivatives that potentially inhibited classical HDAC enzymes. Therefore, we evaluated the Sirtuin inhibition activity of our in-house compound comprised of imidazole derivatives and the strongest inhibition was observed with Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl) acetate against Sirt6 by in-silico and protein expression studies. Our results suggested that Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl) acetate could be a potential novel sirt6 inhibitor.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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