MOLECULAR GEOMETRY, VIBRATIONAL SPECTROSCOPIC, MOLECULAR ORBITAL AND MULLIKEN CHARGE ANALYSIS OF 4-(CARBOXYAMINO)- BENZOIC ACID: MOLECULAR DOCKING AND DFT CALCULATIONS S.N.Saravanamoorthy*,

Structure based biological and chemical properties of 4-(carboxyamino)-benzoic acid has been studied by quantum chemical methods. The revamped geometric structure and its quantum chemical parameters were obtained by DFT-B3LYP/6-311G method. Normal mode analysis is performed to assign the fundamental vibrational frequencies as per the potential energy distribution (PED) by using the VEDA program. Simulation of IR and Raman spectral patterns are observed by refinement of scale factors. TD-DFT approach is used to explore the excited states of molecule and prediction of electronic absorption spectra. NMR chemical shifts of the molecule are determined by the gauge independent atomic orbital method. The molecular docking is performed to recognize the binding energy of the ligand with the dynamic site of protein. In our docking analysis, the protein 5DT6 shows the best results than other three proteins which could be used for further analysis. Further inter and intra molecular interactions, electrophilic, nucleophilic and chemical reactivity sites are found by molecular electrostatic potential, HOMO-LUMO and Global chemical reactivity descriptors. Thermodynamic property of the title compound is also reported. The determined quantum chemical parameters show high reactivity and the dipole moment was sufficiently high enough to induce nonlinear characteristics which are required for applications in optoelectronic devices.


INTRODUCTION
p-Aminobenzoic acid (PABA) shows very important roles in a wide variety of metabolic processes.PABA, a benzene ring with para (carbon 1 and 4) places of amine and carboxylic acid gatherings, is a zwitterion.PABA is a flexible reagent for structure expansion through direct hydrogen holding relationship, through both the carboxylic and amine utilitarian gatherings.The interest in carboxylate builds all in all and a benzoic acid subsidiary specifically keeps on developing as a result of their substance and natural properties.Benzoic acids and their subordinates are significant underlying components for some, regular items, being engaged with different physiological cycles in plants.Among these accumulates, PABA has shown organic, therapeutic and modern interest.PABA is a notable compound of high biological importance and it is present in plant and animal tissues and also sometimes referred to as bacterial vitamin H 1 , B x or B 10 [1].PABA is a well-known forerunner of folic acid [2], and has as of late been recognized as a coenzyme Q precursor [3,4], which opens new possibilities for its application in medicine.It is a structure block utilized in plan of medications and as often as possible found as a design moiety in drugs [5].PABA displays a wide scope of restorative uses as cell reinforcement [6,7], antibacterial [8,9], antimutagenic [10], anticoagulant [11,12], fibrinolytic and immunomodulating specialist [13], defensive medication against UV-illumination [ [14][15][16] and in indicative tests for the condition of the gastrointestinal tract [17,18].Late investigations in agribusiness report the part of PABA in plant thermotolerance [19] and its activity as compound inducer of foundational obtained obstruction against plant microorganisms [20].Viewed as in the B-complex nutrient family and described by security and cost adequacy, PABA is oftentimes added alongside plant chemicals in nutriment media as a trigger of seed germination [21].
Due to the interest in the field of new materials, the chemical structures of organic-inorganic hybrid materials have been extensively investigated.The knowledge of binding energy and energy band gap explains the intrinsic properties like chemical reactivity and electrophilic sites of the compound predicted from quantum chemical calculations.To the best of our knowledge, no detailed quantum chemistry study has been performed for 4-(carboxyamino)benzoic acid.The optimized structure and its geometric parameters are also found.The vibrational studies for each functional group are studied in detail using VEDA4 program.The nonlinear optical materials have potential applications in areas like optical limiting, signal processing, optical logic gates, laser radiation protection, etc. [22][23][24].In addition to these properties, UV spectra, and thermodynamic properties are also examined for the compound.
The suitable computational calculation of DFT has been performed with the help of Gaussian 09W package and the results obtained in the theoretical technique were evaluated.

MATERIAL AND METHODS
The three dimensional atomic design of the title compound for theoretical computational work was downloaded from PubChem site.Every one of the computations was performed on Gaussian 09W programming with DFT method.For direct molecular structure implementation to compute vibrational spectra, DFT-B3LYP/6-311G technique was utilized.
The molecular geometry and vibrational frequencies values of the molecule for title compound in ground state have been determined.

Geometrical structure
The optimized molecular structure of 4-(carboxyamino)-benzoic acid is shown in Figure 1.
The molecular geometry of the title compound is explained in terms of bond lengths, bond It makes an angle of 128.7 The dihedral angle of phenyl group attached to the carboxyamino group ranges from -179.9 to +179.9The theoretical frequencies are presented in Table 1.The absorption through DFT method at 3491 cm -1 is assigned to N-H symmetry stretching mode and 3499 cm -1 is obtained in HF method.Wang and Ma [26] suggested N-H stretching bands in the region, 3365-3374 cm -1 .Generally the aromatic C-H stretching vibration appears weakly between 3120-3000 cm - 1 .But in B3LYP calculations, it gives band in the range 3058-3133 cm -1 .It shows that symmetry stretching mode is active.These four modes are pure stretching modes as is evident from PED column; they almost contribute 95%.The in-plane C-H bending vibrations normally appear in the range 1000-1300 cm -1 in the substituted benzenes and the out-of-plane bending vibrations occur in the region 750-1000 cm -1 region [27,28].In aromatic compounds, the C-N stretching vibration usually appears in the region 1400-1200 cm -1 .The absorption band located at 1331 cm -1 is attributed to C-N stretching vibration.An asymmetric stretching mode of C-N band appears at 1246 cm -1 .Usually, C=N stretching bands appears in the region 1598-1638 cm -1 [26].In the present study, the C=N stretching mode is observed at 1623 cm -1   for HF method.The absorption is touchy for both the carbon and oxygen particles of the carbonyl gathering.Both have the same while it vibrates.Normally, the C-O stretching vibrations occur in the region 1260 -1000 cm -1 [29].In the present study, the C-O stretching vibration is assigned at 1314 cm -1 at B3LYP/6-311G level.The assignments of the COO group vibrations are closely agree with the literature values [30,31].The in-plane COO bending vibration is localized at 839 cm -1 .A very weak COO out-of bending mode is found at 684 cm -1 .The band observed at 960, 871 and 839 cm -1 was assigned to C-C-C stretching vibrations in DFT method.The O-H stretching vibrations are touchy to hydrogen bonding.
The hydrogen bonding alters the frequencies of the stretching and bending vibration.The hydrogen bonding if present in five or six member ring system would reduce the O-H stretching band to 3200-3550 cm -1 region [32].In the computed IR spectrum, a weak band observed at 3573 and 3538 cm -1 are assigned to O-H stretching mode of vibration.The potential energy distribution contribution to these modes is 100%.Abbreviations: ν -h n on ; α -ymm h n ; τtorsion; β -n pl n n n on ; γout of plane bending

UV spectral analysis
The UV spectral analysis represents that the electron absorption corresponds to the transition from the ground state to the first excited state [33].The band gap energy was calculated using h o mul E=h /λ, wh h n on n , λ h u -off wavelength.The theoretical excitation energies, absorption wavelength and oscillator strength are summarized in Table 2.
The UV spectrum of the title compound is shown in Figure 4. Energy gap were determined at the B3LYP/6-311G level utilizing TD-DFT approach in gas phase.These transitions are based totally on the groundwork of fundamental contribution of molecular orbitals.The o l on u on ≤ % n l [34].In this case, the strong transition was observed at nm with maximum oscillator strength f=0.6462 with 4.41 eV energy gap and from HOMO-LUMO diagram is 5 eV.The other transitions are found at 258, 272 nm.UV visible spectra show that entire transitions belong to the quarts ultraviolet region (240-340 nm).So the compound can be used for quarts optics [33].The peak was observed at 281 nm wh h w u o h p n o wo π onju y m o on ( =N, =O n h compound.It was evidence that the present compound is able to produce the optical energy with second and third fold frequency.The group contributions to the molecular orbital and the density of state (DOS) are found using Gauss-sum 2.2 program [35].The calculated TDOS diagram of the title molecule is shown in Figure 5.The DOS spectra were created by convoluting the molecular orbital information with Gaussian cures of unit height [36].

Parameters of NLO properties
When electromagnetic fields interact with various media, it produces new fields with changes in frequency, phase, amplitude, or other characteristics of the incident fields resulting nonlinear optical (NLO) properties [39].The total hyperpolarizability (β tot ) is the significant boundary to assess the NLO susceptibility.It means that the ompoun w h l lu o β tot is predicted to be a potential NLO active one and vice versa [40].NLO behavior of compounds can be easily perceived and understood using theoretical calculations.Therefore, hyperpolarizabilities 〈 〉 are defined using the x, y, z components as [41][42][43].
For the (hyper)polarizabilities, the calculated values are in atomic units throughout the work.

FMO Analysis
According to FMO theory, HOMO and LUMO are important terms in quantum chemistry that reflect the bioactivity of compounds.The HOMO particularly donates electrons, while LUMO represents the ability to gain an electron.Thus, studies on FMO provide some useful information for physicists and chemists about the active mechanism [44].Molecular electrostatic potential (MEP) is important to characterise inter and intra molecular electrostatic interactions [47].The charge spreads over the surface can be used to determine the interaction of nonlinear active molecules as well as to determine the type of chemical bond [48].MEP is essential in structural biology to determine ligand-substrate interactions, drug-receptor and enzyme-substrate interactions [49].To predict reactive molecular sites, the 3D map of the molecular electrostatic potential (MEP) surface was plotted for the total electron density of the title compound and is shown in Figure 9.The electrostatic potential contour surface of the title molecule is presented in Figure 10.The different values of the electrostatic potential at 3D map are mentioned by different colours.In Gauss View, the colour code in 3D map varies between -7.113 a.u. and +7.113 a.u.The red colour region (negative electrostatic potential) is related to electrophilic attack while the blue colour region (positive electrostatic potential) represents nucleophilic attack [50].It has been revealed through Figure 10

Mulliken atomic charges
The Mulliken atomic charge is directly related to the vibrational properties of the molecule and chemical bonds present in it.And also it shows that improved numerical stability and portrays the distribution of electrons in a better way [51].Mulliken atomic charges affect the dipole moment, polarizability, electronic structure and more properties of molecular system [52].Figure 11

Force constant and reduced masses
The force constant and reduced mass of 4-(carboxyamino)-benzoic acid molecule calculated using DFT-B3LYP/6-311G and are shown in Figure 12 and 13.In Figure 12, Force constant can be divided into two regions; the first part range is from 0 to 1600 cm -1 .The second part range is from 1600 cm -1 to near 3700 cm -1 .The highest force constant value is 13.92 mDyne/A .In Figure 13, the title molecule has highest reduced mass at 9.33 a.u.According to the formula √ , the reduced mass is inversely proportional to the frequency and force constant is directly proportional to the frequency.Figure 12 and 13 shows that the values of reduced mass are decreasing and force constant are increasing.

Donor-acceptor interactions
NBO is an efficient method to understand the intra and inter-molecular non-bonded interactions for bio-molecular compounds.Table 5 shows the occupancy and energies of i and j orbitals with the of the most significant lone pair (LP) and bonding ( /π) to antibonding ( */π*) transitions.Some significant orbital interactions and corresponding second order perturbation energies derived from the NBO computation for the compound 4-(carboxyamino)-benzoic acid.The Donor-acceptor interactions are happened between filled Lewis and empty non-Lewis NBOs after estimating their energies through second order perturbation theory.These interactions are termed " lo l z on" o on o h zeroth-order natural Lewis structure.The energy of these delocalization interactions E( 2) is proportional to the NBO interacting intensities and energies which gives the interactions among various parts of the molecules [53][54][55].For each donor (i) and acceptor (j), the interaction energy E(2) was obtained from the standard second order perturbation approach .Where the term q i refers the occupancy of donor orbital, E i and E j denote the energies of donating and accepting orbitals and F(i,j) 2 is the KS matrix (Fock matrix) between i and j NBO orbitals.

Reduced gradient of density (RDG)
By employing NCI analysis, it is possible to determine the nature of the interactions based on electron density and the sign of the second derivative in the perpendicular direction of the bond (λ2).RDG density is a dimensionless quantity and is written in the following form [56]:  properties of chemical compounds.On the basis of vibrational analysis at DFT-B3LYP and HF methods with basis set 6-311G and 6-31G level, the standard thermodynamic functions heat capacity, entropy, enthalpy, zero point vibrational energy, thermal energy and dipole moment for the title compound were found from the theoretical harmonic frequencies and presented in Table 6.These parameters obtained here give available information for the further studies on the title compound and also estimate directions of chemical reactions according to the second law of thermodynamics.The ZPVE is lower in DFT/6-311G than HF/6-31G.Variations of the ZPVE seems to be important [57][58][59].The biggest value of ZPVE of the title compound is 100.78414Kcal mol −1 .As a result of HF method calculation the highest dipole moment was 2.6123 Debye.The highest values of specific heat capacity and entropy were gotten for B3LYP/6-311G method.From the analysis of docking score and energy, the protein 5DT6 showed the best results than other proteins.between the title molecules.Thus, the present investigation provides a complete and reliable structural, spectral and biological activity of the compound.This investigation presents these features of 4-(carboxyamino)-benzoic acid for the first time, but also prepares the ground for future investigations.

10 − 65
C 4 m 4 J −3 .For B3LYP/6-311G, the calculated first order hyperpolarizability (β tot ) is 281.63 × 10 −53 C 3 m 3 J −2 and average second order hyperpolarizability is -0.7693 × 10 −61 C 4 m 4 J −3 .Urea is the prototype molecule generally considered as a reference for the comparison of good nonlinear optical properties.The first-order static hyperpolarizablity of title molecule is two times greater than that of urea (β tot = 138.365× 10 −53 C 3 m 3 J −2 ).It shows that title molecule is good candidate as materials for applications in nonlinear optics.

Table 4 :Fig. 8 :
Fig. 8: The graphical representation of the FMOs 3.7.Molecular electrostatic potential Analysis that there are four possible sites for electrophilic attack.As can be seen from the Figure, the negative region is mainly localised over oxygen atom.It is the most propitious site for electrophilic attack having the values -0.02 a.u. to -0.05 a.u.The nucleophilic attacks are around the hydrogen atoms with values in the range 0.05 to 0.0634 a.u.The maximum positive value 0.0634 a.u corresponds to the hydrogen atom (H20) of carboxyl group attached with Oxygen (O3).

Fig. 9 :Fig. 10 :
Fig. 9: 3D map of the molecular electrostatic potential (MEP) represents the atomic charge distribution of the title compound for B3LYP/6-311G basis set.Atomic charges of all carbon atoms are negative except C6, C12 and C13; those are bonded with nitro and carboxylic acid groups.Due to the reason of electronegative atoms attached with the carbon atoms pull out the partial charges from these atoms.Hence these carbon atoms become positive charges.The extremely maximum protonated and deprotonated atoms are C13 (0.655 e) and N5 (-0.795 e) respectively.All the hydrogen atoms acquire positive Mulliken atomic charge.The charge distribution shows that O1, O2, O3 and O4 are negatively charged.The biggest value of charge (0.402 e) is noticed for H20 may be due to hydrogen bonding.

Fig. 11 :
Fig. 11: The atomic charge distribution of the title compound for B3LYP/6-311G basis set

⁄
We have represented, in Figure13, a 2D plot of RDG, as a characteristic of the electron density accelerated by means of the signal of the second eigenvalue of the matrix of Hessian.λ2 is the greatest eigenvalue of the Hessian matrix which characterizes the fluctuation of the density in the vicinity of the critical point.From the value of the sign (λ *ρ, w n distinguish between the one kinds of non-covalent interactions.The -λ2 confirms a bonding interaction, such as hydrogen bonds, whereas +λ2 shows nonbonding interactions and Vander Waals interactions can be determined by negligible values of λ2.According to figure 14, the red, green and blue circles indicate repulsive interactions (steric effect), VDW and H-bond respectively.Generally, VDW interactions have very low electron densities.The regions of interactions corresponding to the hydrogen bond and the repulsive interactions have a high density.The blue circle confirms H-bond formation between the title molecules.

Fig. 14 :
Fig. 14: Graphical representation of the reduced density gradient versus the electron density

Table 2 :
The theoretical excitation energies, absorption wavelength and oscillator strength fourth rank tensor.It is known as third-order NLO coefficient.The nonlinear parameters of the title compound are calculated by using DFT theory based on the finite field approach and HF method.The nonlinear parameters are reported in Table3.The o ompon n (β µ ) and average second order hyperpolarizability 〈 〉 are normally theoretical correlation between the structure of the compound and NLO property may suggest the possibilities of design and synthesis of new NLO materials.First order

Table 5 :
Stabilization energies obtained from the most significant lone pair to antibonding transition of the compound 4-(carboxyamino)-benzoic acid

Table 6 :
Calculated thermodynamic parameters using HF/6-31G and DFT-B3LYP/6-311G methods These molecular properties were determined by using Molinspiration software.This web tool is freely accessible (https://www.molinspiration.com).The assessed druglikeness properties of the title molecule are recorded in Table7.The bioavailability score is obtained to be 0.56.This shows that the title molecule is a better candidate for biological properties and hence applied for docking studies.Medication applicants ought to have ideal ADMET prediction.The ADMET for title molecule is obtained utilizing the pkCSM-ADME program which is freely accessible through web tool (http://biosig.unimelb.edu.au/pkcsm/).

Table 8 .
[65][66][67]rmeability and low permeability for skin is resolved to assess the absorption of title compound were obtained to be 0.0643 ns m -1 and -2.735 log kp.The Human Intestinal Absorption is the most important factor for a drug molecule which usually lies between 70 to 100%.It determines good intestinal absorption for drug molecules.The HIA value of title molecule was found to be 97.63%, which is well absorbed for the human body[62,63].The limitation of a drug to enter the brain is a critical limit that ought to be considered to decrease side effects and toxicity and the measured value for the title molecule is -0.824[64].The value of skin permability is -2.735 which specifies that the compound cannot be absorbed by human skin.The pure water solubility was found to be low value The toxicity of the AMES exhibiting negative shows that its non-cancer and nonmutagenic molecule.It does not inhibit hERG-I and hERG-II and also does not cause skin sensitivity.T.pyriformis Toxicity and minnow toxicity of the title compound was determined to be 0.282 log ug/L and 2.525 log mM[65][66][67].Every one of the parameters result mentions that the title molecule has been the biological activity of the drug in future.

Table 7 :
[68]nspiration property values of 4-(carboxyamino) benzoic acid Elec.Whereas, VDW is vander Waal energy, Hbond and Elec are hydrogen bonding energy and electro static energy respectively[68].Table9described the docking result of 4-(carboxyamino)-benzoic acid with four target proteins using iGEMDOCK.The docked poses of the compound with four target proteins were represented in Figure15, 16, 17 and 18.For molecular docking, the protein 3UOW, 4WIN and 4WIO are GMP Synthetase binding protein from Plasmodium Falciparum which is essential to causative agent of the fatal form of malaria.GMPS is a vital protein in the purine biosynthetic pathway.Protein 5DT6 is glutamine receptor.The binding energy between compound and proteins 5DT6, 4WIO receptors are found to be -99.0424and -95.151 respectively.In the interaction state of title molecule with 4WIN receptor, the binding energy of corresponding receptor is found to be -87.7694.The highest binding energy of 4-(carboxyamino)-benzoic acid is observed against 3UOW with a binding energy of -69.6664.The best molecule has the lowest binding energy.