key: cord-0970672-n1awfzb1 authors: .Deephlin Tarika, J. D; Divya Dexlin, X. D.; Madhankumar, S.; Deva Jayanthi, D.; Joselin Beaula, T. title: Tuning the Computational Evaluation of Spectroscopic, ELF, LOL, NCI Analysis and Molecular Docking of Novel Anti COVID-19 Molecule 4-DimethylaminoPyridinium 3, 5-Dichlorosalicylate date: 2021-05-05 journal: Spectrochim Acta A Mol Biomol Spectrosc DOI: 10.1016/j.saa.2021.119907 sha: 9a4cd8aaa66accc21b057782a70a698efc9d2dcd doc_id: 970672 cord_uid: n1awfzb1 In this work novel antiviral compound 4-(Dimethylamino) Pyridinium 3, 5-dichlorosalicylate was synthesized and characterized by UV-vis, FT-IR, FT-Raman,1H NMR and 13C NMR spectra. Quantum chemical computations were carried out by Density functional theory methods at B3LYP level. Electronic stability of the compound arising from hyper conjugative interactions and charge delocalization is investigated using natural bond orbital analysis. Assignments of vibrational spectra have been carried out with the aid of Normal coordinate analysis following the SQMFF methodology. TD-DFT approach was applied to assign the electronic transition observed in UV visible spectrum measured experimentally. Frontier molecular orbital energy gap affirms the bioactivity of the molecule and NCI analysis gives information about inter and intra non covalent interactions. ESP recognises the nucleophilic and electrophilic regions of molecule and the chemical implication of molecule was explained using ELF, LOL. The reactive sites of the compound were studied from the Fukui function calculations and chemical descriptors define the reactivity of the molecule. Molecular docking done with four Covid 19 proteins endorses the bioactivity of molecule and drug likeness factors were calculated to comprehend the biological assets of DADS. Pyridine is pondered to be privileged ligands in medicinal chemistry since their derivatives or analogues have been publicised to exhibit a surfeit of biological deeds, including anti-cancer, antiviral, antibacterial, antifungal, antioxidant, antimicrobial, antidiabetic and antiinflammatory properties [1] . Biological exploit of these molecules is mainly attributable to formation of hydrogen bond among the target and electrons of lone pair in a sp 2 hybrid orbital of nitrogen atom [2] . Pyridine moieties are often used in drugs owing to their characteristics such as basicity, water solubility, stability, hydrogen bond-forming ability and their small molecular size. Replacement of pyridine moieties by amines, amides, heterocyclic rings containing nitrogen atoms and benzene rings are important in drug discovery owing to their ability to act as bioisoters [3] . Dichlorosalicylic acid a colourless crystalline organic acid is used as a Keratolytic, Comedolytic and Bactereolytic agent in treatment of warts, Psoriasis, acne, ringworm and dandruff [4] . Salicylic acid derivatives are most widely used as an antiinflammatory drug [5] and also found in plants with role such as plant growth, photosynthesis transpiration, ion uptake and transport [6] . A deep knowledge of intrinsic properties of titled compound is required to understand the reactivity involved in binding reactions. A thorough survey of the literature reveals that so far there is no detailed experimental and theoretical study on 4-Dimethylamino Pyridinium 3, inspires to do the Quantum chemical calculations in order to confirm its biological activities. Redistribution of electron density (ED) in various bonding, antibonding orbitals and E (2) energies are calculated by natural bond orbital (NBO) analysis. Electronic properties of DADS are scrutinised using frontier molecular orbital (FMO) energies and UV spectral analysis using Time dependent (TD) DFT (density Functional Theory) method. DADS have been characterized by FT-IR, FT-Raman, NMR (Nuclear Magnetic Resonance) techniques to identify and study the activity of organic compound. Topology analyses were made on the basis of ELF (electron localization function) [7] and LOL (localized orbital locator) maps obtained from Multiwfn 3.4.1., a wave function analyser [8] . Fukui functions and chemical reactivity descriptors were calculated to study the reactivity of molecule and most reactive sites were also revealed. Drug likeness and molecular docking approach are enabled to check pharmaceutical potential and bioactivity of DADS. Analytical grade, 4-(dimethylamino)pyridine (DA) and 3,5-dichlorosalicylic acid (DS) were taken in 1:1 stoichiometric proportions are dissolved homogeneously using methanol as a solvent and reaction mixture was thoroughly mixed together using mechanical stirrer up to 6 hours at 30˚C. The synthetic scheme of DADS was depicted in Figure 1 . The clear pale yellow coloured solution obtained was filtered to remove the impurities and was kept aside for about a week to get the crude product. Slow evaporation-solution growth technique was used to grow single crystals. The pure raw material was dissolved in minimum quantity of methanol, stirred for a few hours, filtered through a quantitative filter paper (Whatman no.40) and filtrate was kept aside without any disturbance for the growth of crystals in a dust free environment at ambient temperature. Bright, transparent, pale yellow coloured DADS crystals were obtained after 10 days and the crystals were collected carefully from the mother liquor. The harvested crystals were recrystallized repeatedly to get superior quality crystals. Spectroscopic profiling of DADS was carried out with Becke3-Lee-Yang-Parr (B3LYP) level with 6-311 G** basis set [9] using Gaussian'09 program package [10] . NBO analysis has been performed on a molecule at the same level using second order Fock matrix and atomic natural charges is also been calculated by NBO method [12] . Normal coordinate analysis (NCA) had been executed using MOLVIB program version 7.0 written by Sundius in order to obtain thorough interpretation of the fundamental modes [13, 14] . In accordance to scaled quantum mechanical procedure (SQM) using selective scaling in the natural internal coordinate representation, scaling of the force field was performed to obtain a better concurrence between the theory and experiment [14] . NMR chemical shifts have been calculated with the gauge including atomic orbital (GIAO) approach and compared with experimental spectra to know about chemically significant area. Gauss view 5.0 software [15] is used to obtain highest occupied and lowest unoccupied molecular orbital maps (HOMO-LUMO), band energy gap and molecular electrostatic potential map (MEP) for identifying the potential region. Non Covalent Interaction (NCI) analysis, ELF, LOL, Fukui function were carried out by Multiwfn [8] which is a multifunctional wave function analysis program and all isosurface map were rendered by VMD program [16] . Thermodynamical properties for various temperatures are calculated using the perl script Thermo.pl [17] . Autodock suite 4.2.1 was used to find the minimum binding energy, Inhibition constant and various parameters of ligand-protein interactions [18, 19] . The optimized geometric parameters computed using DFT method of DS, DA, DADS are portrayed in Table 1 & dihedral angles in Table S1 whereas atomic numbering scheme of DS, DA, DADS molecule obtained by DFT computation is exhibited in Figure 2 . Selfconsistent force field energies for DS, DA and DADS were obtained as 1415.4025, -382.3537, -1797.7807 eV respectively. BSSE and counterpoise corrected energy for DADS have been calculated as 0.003969 and -1797.7767 eV. Phenyl ring appears to be little distorted ascribed to substitution of chlorine atoms which slightly proliferates the bond angle C 4 -C 5 -C 6 (121°) than hexagonal angle 120°. Bond angles C 1 -C 2 -O 11 (123°) and C 3 -C 2 -O 11 (118°) significantly deviate from the contemplated trigonal angle (120°) as an effect of attachment of electron donating hydroxyl group instead of hydrogen atoms. (2.72 Å) which is shorter than van der Waals separation between N and H atom (3Å) [20] . Abatement in C 17 -N 22 -C 21 angle (116.4°) is by dint of steric interaction which arises in virtue of intermolecular hydrogen bonding interactions. Bioactive molecules exert biological activity through hydrogen bonding interactions with their biological targets [21, 22] bonds around 4 th position of π deficient pyridine ring. Electron density of aromatic system is increased due to the hyper conjugation of dimethyl amino group with ring [24, 25] .The heterocyclic ring appears to be crooked because of the dimethyl amino group substitution which is scrutinized from the bond angle of C 20 -C 19 -C 18 (116°) smaller than typical hexagonal angle 120°. In pyridine ring, bond length of C atoms attached with amino group C 19 -C 20 , C1 9 -C 18 is found to be larger than the bond distances of C 20 -C 21 , C 21 -N 22 , N 22 -C 17 and C 17 -C 18 due to the effect of substitution of dimethyl amino group in the place of hydrogen. C-N bond length calculated as 1.365 Å is shorter than the normal C-N bond length 1.480 Å and shortening of this C-N bond length reveal the effect of resonance in dimethyl amino group [26] . Internal C 17 -N 22 -C 21 angle (116.4°) of protonated N atom is significantly less than other nearby two angles C 20 -C 21 -N 22 (124.2°) and C 18 -C 17 -N 22 (124.2°) within the ring in virtue of steric effect of the lone-pair electron predicted by valence-shell electron-pair repulsion theory, VSEPR [27] . The dimethyl amino group oriented in pyridine ring with antiperiplanar conformation as indicated by the torsional angle C 18 -C 19 -N 27 -H 31 (-179.3°). The carboxylic group of phenyl ring and dimethyl amino group of pyridine ring are found to be out of plane as indicated from the torsional angle C 3 -C 3 -C 13 -C 14 (90.9°), C 3 -C 4 -C 13 -C 15 (-89.36°), C 5 -C 4 -C 13 -C 14 ( -87.17°), C 19 -N 27 -C 28 -H 29 (-61.403°), C 19 -N 27 -C 28 -H 31 (60.08°), C 19 -N 27 -C 32 -H 33 (-60.41°) [28] . NBO analysis is a cardinal tool which lucubrate the intra and intermolecular bonding interactions scrutinizes charge transfer or conjugative interactions in molecular systems. Second order Fock matrix was carried out at the B3LYP method to evaluate the donor-acceptor interactions in the NBO analysis is portrayed in Table 2a and composition of H-bonded NBOs in terms of natural atomic hybrids is portrayed in Table 2b . 0.01647 3.10 1.28 0.056 σ(C 1 -C 2 ) 1.97229 σ * (C 2 -C 3 ) 0.04243 4.98 1.23 0.070 π(C 1 -C 2 ) 1.61982 π * (C 3 -C 4 ) 0.42943 18.29 0.28 0.064 π(C 1 -C 2 ) 1.61982 π * (C 5 -C 6 Table 2a . The σ and π electron bonds of (C 1 -C 2 ), (C 3 -C 4 ), (C 5 -C 6 ) shows double bond characteristics whereas (C 1 -C 6 ), (C 2 -C 3 ) and (C 4 -C 5 ) shows only single bond characteristics which was portrayed in Table 2a . Electron density of conjugated double as well as single bond of phenyl ring clearly demonstrates strong delocalization inside the molecule. Pyridine ring atoms have weaker stabilization energy than phenyl ring atoms which is evident from Table 2a , in virtue of negative inductive effect of nitrogen atom, electron density is not evenly distributed over the pyridine ring [29] . As per the resonance structure of pyridine, only C 17 Occupancy of C-C bonds with σ and π (1.6 e) bonds are lesser than the C-C bonds with only σ (1.9 e) bonds since the electronegativity of sp 2 hybridized carbon atom is greater than sp 3 hybridized atom [31] . C-O bond of carboxyl group has lesser energy transfer to the antibonding C-O, since the oxygen atom of hydroxyl group has lost 'full-control' of this lone pair and the oxygen atom of the CO group has acquired a small share of this lone pair. The greater electron-attracting power of oxygen in a hydroxyl group over that of an oxygen atom alone is due to hydrogen atom which forms the bond, and thereby decreases the electron density on that oxygen atom [32] . In DADS a very resilient interaction has been observed between the Acidity of the donor C-H group and its potential hydrogen bond donor strength increases in passing from sp 3 over sp 2 to sp hybridized C atoms and is also increased by surrounding electron withdrawing atoms is confirmed in C 17 -H 23 bond at C 17 passing from sp 2.48 to sp 2.53 hybridized in DADS to DA respectively. The aspiration of vibrational analysis is to find out vibrational modes associated with Table S2 and S3. The assignments of DADS with potential energy distribution (PED) have been reported to know the maximum probability of vibrations in Table 3 and observed FT-IR and FT Raman spectrum along with the simulated spectra is shown in Figure 3 and 4 for visual comparison. Aromatic structure shows the presence of C-H stretching vibrations in region 3100-3000 cm -1 , the characteristic region for ready identification of C-H stretching vibrations [34, 35] are not affected appreciably by nature of substituents. The scaled wavenumber for C-H stretching fall in the range 3070 cm -1 and 3053 cm -1 with 99% PED is observed at 3071 cm -1 , 3052 cm -1 in IR and at 3065 cm -1 , 3052 cm -1 in Raman are assigned to C-H stretching vibrations. The C-H in plane bending frequencies which is useful for the characterization purpose appears in the range 1000-1300 cm -1 is observed at 1110 cm -1 ,1176 cm -1 in FT-IR and at Vibrational analysis of carboxylic acid was carried out giving preference to carbonyl group which are significant for the antiviral activity of the compound. C=O stretch bands appear in region 1710-1680 cm -1 depends on the physical state, electronic, mass effect of neighbouring substituents, conjugation, intra-molecular and intermolecular hydrogen bonding [42] is observed at 1703 cm -1 in FT-IR agrees with the scaled value at 1708 cm 1 . Carboxylic acid also contains a C-O band and the C-O stretch of carboxylic acid appears between 1320 cm -1 and 1210 cm -1 and for DADS the C-O stretching vibrations is observed at 1273 cm -1 in FT-IR agrees with the scaled value at 1273 cm -1 . O-H bond is highly polar because of large electronegativity difference between oxygen and hydrogen. The spectral bandwidth of hydroxyl group is greater than other functional groups due to the chemical environment caused by hydrogen bonding [41] . DADS molecule possesses a CH 3 group in 2 positions and nine fundamentals can be associated to each CH 3 group for the assignments of CH 3 group frequencies. Based on the orientation of DADS methyl groups are supposed to vibrate more elastically than pyridine ring. Normally CH 3 asymmetric and symmetric stretching vibrations are found at 2962 cm -1 and 2872 cm -1 [43] . Strong absorptions in FT-IR at 2810 cm -1 is assigned to the asymmetric CH 3 stretching modes and the symmetric stretching is identified in FT-IR at 2975 cm -1 . The changes in CH 3 stretching mode is due to the influence of electronic effects resulting from hyper conjugation of methyl group with nitrogen atom and the aromatic ring system which points to change in polarizability and dipole moment due to electron delocalization [41, 23] . Thus the hyperconjugation of methyl group, causing changes in IR, clearly evinces that methyl hydrogen is directly involved in the donation of electronic charge. is less sensitive to changes in molecular structure than the C-H stretching. CH 3 rocking mode vibration is expected to occur in region 1070-900 cm -1 [45, 46] is observed in FT-Raman spectra 1023 cm -1 . ( 22), τ HN ( 17) 80 τ CN ( 41), τNC( 15), τ NC ( 14), τ as R2 ( 12), τ' as R2 ( 11) 74 τ OC ( 15), τ' as R1 ( 14), ρCO ( 13), ω R1 CC ( 12) 64 τ' as R2 ( 60), τ as R2 ( 14), R2P ( 12) 58 ʋ NH ( 67), ʋ OH ( 20) 44 τ HN ( 29), τ OH ( 26), τ' as R2 ( 11) 15 τ HN ( 57), τ' as R2 ( 12) w: weak, s: strong, m:medium, ν:stretching, ν ss: symmetric stretching, ν as: asymmetric stretching, δ: deformations (SD: symmetric, AD: asymmetric, ADO : asymmetric out of plane RD: ring, TD: trigonal), τ: torsion, τ as : Asymmetric torsion , τ' as :Asymmetric torsion out of plane R1: Ring1, R2: Ring2, β: bending, ρ: rocking, ω:wagging, P: puckering, S: Scissoring. Aromaticity is an axiomatic concept in organic chemistry enacts an important role in ordaining the structure, stability and reactivity of molecules [47, 48] . The geometrical aromaticity of homocyclic and heterocyclic compounds can be evaluated by harmonic oscillator model of aromaticity (HOMA) index value. HOMA index value for phenyl ring found to be 0.984 is slightly lower than the ideal value of aromaticity due to replacement of hydrogen atoms by chlorine and hydroxyl group in benzene ring. For the pyridine ring HOMA index value found to be 0.9350 and this slight accrual in aromaticity is due to the substitution of dimethyl amino group. HOMA index of pyridine is lower than phenyl ring ascribed to H-bonding interactions and the protonationinduced delocalization. From the HOMA index value of both the phenyl and pyridine ring it is concluded that both these rings are aromatic in nature. In order to evaluate the energetic behaviour of DADS the frontier orbital calculations were topped off by means of B3LYP method. The FMO's were delineated in Figure 5 where positive phase is exposed in green and negative is depicted in red which embodies the charge transfer within the molecule. Atom occupied by more densities of HOMO should have stronger ability to detach electron whereas the atom with occupation of LUMO should have the dexterity to gain electron [49] . It is grasped from the HOMO plot that charge density is localized over the Phenyl ring, Chlorine atom, hydroxyl group whereas LUMO is spread over the carbon atoms pyridine and phenyl ring. Table 4 and UV spectra is depicted in Figure 6 . Oscillator strength f is a dimensionless quantity that describes the strength of an electronic transition [51] and the oscillator strength for the transition at λ max 268 nm is higher in magnitude than the other transitions which agrees with the experimental absorption value 270 nm corresponds to π -π * transition. The band energy gap for the observed λ max found to be 4.626 eV agrees with the frontier orbital band gap is found to be 4.9329 eV and the band energy gap of DADS molecule confirms its biological activity by intermolecular charge transfer [52] . Electronegativity(χ), hardness (ղ), softness (S) are commonly used as global reactivity parameters within DFT. Energy of frontier molecular orbitals HOMO and LUMO, ∆E and global reactivity parameters for compound DADS calculated at B3LYP level are listed in Table 5 . Hardness of a molecule is related to gap between frontier molecular orbitals and global softness is inverse of global hardness [53] . Negative value of chemical potential evinces that compound is stable and does not decompose spontaneously into its elements. Stability of compound is endorsed by chemical hardness which measures 2.4664 eV and competency to attract the shared electrons which describes the electronegativity of compound is found to be 3.4106 eV. The scope of compound in medical and industrial field can be ascertained using the chemical softness value estimated to be 0.4054 eV indicates the non toxic nature of the molecule. Electrophilicity index italicizes the biological activity, confirms the pathway for molecular docking approach with different protein targets [54] . Atomic natural charges calculated by NBO method are portrayed in Table S4 and atomic natural charges are depicted in Figure 7 . All carbon atoms extant in phenyl ring are positive except C 2 atom, which is negative due to attachment of the hydroxyl group. Hydrogen atoms in the phenyl ring are found to be equally positive due to sharing of electrons with nearest carbon atoms. Electron withdrawing groups increase positive charge on the hydrogen atom of the interacting C-H bond, which increases attractive electrostatic interaction with phenyl ring. Charge of hydrogen H 12 in O-H group is massive than other hydrogen atoms due to the hydrogen bonding interaction and the oxygen atom which take part in this interaction has more negative charge. C 2 atom is negative due to the attachment of hydroxyl group in the place of hydrogen atom. Cl 9 atom is found to have high negative charge and massively small positive charge is found in Cl 10 atom since it is switched in the place of hydrogen atoms. The chlorine atoms are most preferable site for electrophilic attack and this is also confirmed from the Fukui analysis. In the pyridine ring carbon atoms C 17 , C 19 and C 21 attached with the nitrogen atoms N 22 and N 27 are positive while other carbon atoms are negative. Influence of methyl group electronic effect resulting from hyper conjugation interaction of methyl group of the dimethyl amino pyridine moiety causes negative charge as noticed in C 28 and C 32 atoms. MEP is very important tool to investigate and correlate between the molecular structure and the physiochemical property relationship of molecules including biomolecules and drugs. Knowledge of charge distribution can be used to arbitrate how molecules interact with one another and also used to identify sites for intra and intermolecular interactions [55] . Electron density-based local reactivity descriptors such as Fukui functions were proposed to provide information about chemical selectivity or reactivity at a particular site of a chemical system [58] . Condensed Fukui functions are investigated to indicate the dexterity of each atom in a molecule to serve as a reactive site. Morrel et al have proposed a new dual descriptor ∆f(r) for the identification of molecular site prone to electrophilic and nucleophilic attack [59] . The isosurface plot for f -, f + , f 0 and dual descriptor are shown in Figure 9 and Fukui functions are portrayed in Table S5 . From the isosurface plot blue colour bespeak negative region prone to electrophilic attack and nucleophilic attack is represented by the positive green region. Phenyl ring is prone to electrophilic attack owing to the delocalized pi electrons which behaves as source of electrons and the chlorine atoms (Cl 9 & Cl 10 ) attached to the phenyl ring are the most favourable site for electrophilic attack. Due to the electronegative nitrogen atom pyridine ring is electron deficient and it is more prone to nucleophilic attack. MEP map also confirms that pyridine ring is prone to nucleophilic attack and nucleophilic attack takes around the oxygen atoms. The electronegativity of the carbon, oxygen and nitrogen atoms are greater than the hydrogen atoms, making the hydrogen atoms electron deficient and prone to nucleophilic attack [60] . of phenyl ring and amino group act as a nucleophile due to the electron density around the carbon atoms. The reactivity descriptors of DADS act as a forerunner to uphold the biological activity of the compound through molecular docking [54] . Figure 10 where the relief map with large or contracted peak area delineates the electron environment around each atom. ELF and LOL have homogenous chemical content because they hinge on kinetic energy density. ELF explains the electron pair density whereas LOL explains maximum localized orbitals overlapping due to gradient of orbitals [7] . ELF map is designed in the range 0.0 to 1.0; however region below 0.5 shows delocalized electronic region [60] and the LOL attains large values > 0.5 in regions where electron density is dominated by electron localization [61] . NMR technique elucidate about the unknown structural, chemical and magnetic properties of organic molecules [62] . The combined use of NMR and computer simulation methods offers a powerful way to interpret and predict the structure of large biomolecules [63] . Experimental 13 C and 1 H NMR spectra were recorded in DMSO solvent and calculated in the same solvent using GIAO method. The experimental 13 C and 1 H NMR spectra are depicted in Figure 11 and chemical shift values are portrayed in NCI analysis is implemented to explore the intra and inter non-covalent interaction in a molecular system. The region of these interactions and their graphical visualization is provided using the Reduced density gradient (RDG) analysis based on the electron density and its derivatives. Graphical representation of ρ(r) versus sign (λ2) ρ, where sign (λ2) ρ is the second eigen value of electron density, provides convenient information regarding strength and nature of interactions. The repulsive, attractive and van der Waals (VDW) interactions correspond to sign( λ2) ρ> 0, sign( λ2) ρ< 0 and sign( λ2) ρ≈0, respectively [68] . 2D scatter plot and the 3D RDG isosurface densities of DADS are depicted in Figure 12 . which is also seen from the RDG graph where more green spikes appear between 0.005 to -0.015 a. u. Thermal characteristics of DADS crystal was studied by using TG-DTA under nitrogen atmosphere at a heating rate of 10 °C/min from 30 to 500 °C and TG-DTA thermogram is depicted in Figure 13 . Thermal analysis validates the applicability of DADS for any biological applications. It is important to have knowledge on the temperature dependence of titled compound since the reactivity of compound may vary with temperature [70] . Standard statistical thermodynamic functions such as heat capacity, entropy, enthalpy changes were computed. Thermodynamic properties for various temperature from 100 K to 1000 K is tabulated in Table S6 and the correlation graph between these thermodynamic properties and temperature T are shown in Figure 14 . It is observed from the table that gradual increase in thermodynamical parameters with respect to temperature is due to equipartition energy. The gradual increase in heat capacity shows that system attains more kinetic energy to improve the strength of the vibrations and enthalpy change produce the chemical reaction in DADS [71] . The linear fitting equations with fitting factors (R 2 ) are deduced for the three The thermodynamic data supply useful information for further study of DADS and systematic literature reports reveal that the entropy (S), which focuses on in a biomedical system, drives the direction of all chemical reactions towards disorder. The inferences obtained from above thermodynamic parameters (S, Cp, H) may help to obtain other relation of thermodynamic energies [72] respectively. Together, thermodynamic studies will progress fundamental understanding of molecular interactions and will enable new and improved strategies for successful drug discovery. Molecular docking is an alluring scaffold to know about the drug bio molecular interactions for the rational drug design and discovery. It predicts the binding mode and type of interaction between active site proteins and ligand along with their distance and vicinity of functional groups involved [73] . In order to study the antiviral activity of the DADS docking was done into the active sites of the target proteins namely SARS-CoV-2 proteins (6M03, 6M2N, 7CHF), MERS virus protein (6VGY) and the docking parameters such as binding energy, inhibition constant are listed in Table 7 . PDB structures of the target protein are downloaded from the RCSB protein data bank (https://www.rcsb.org/pdb/home.do). The autodock tools graphical user interface was used to prepare the protein by removing water, adding polar hydrogens, required charges and the preparation of ligand with minimum energy for docking was done. Molecular docking of ligand DADS with the SARS-CoV-2 and MERS virus proteins are depicted in Figure 15 . Ramachandran plot for four docked SARS-CoV-2 and MERS virus protein portrayed in figure 16 evinces 90% of the amino acids lie in allowed region represented by red colour and only very few lie in disallowed region which indicates the stability of the protein chosen for the binding interaction [74] . The antiviral activity of DADS is confirmed in virtue of its good binding affinity with SARS-CoV-2 and MERS virus proteins and so it is suggested that DADS can be a good candidate for the treatment of certain viral disease including Corona diseases. The feedback on drug likeness constraints directs the non-toxic and organically dynamic nature of the title compound. Assessment of drug likeness is influential to find out the compounds which are not ample to be a dynamic drug. There are few important parameters used in identifying the drug likeness property of the compound such as hydrogen bond acceptors (HBA) number, hydrogen bond donors (HBD) number, rotatable bonds, logP, and molar refractivity [75] . All of these parameters constitute the drug likeness test and the values corresponding to the antiviral drug DADS is tabulated in Table 8 . The constraints of drug likeness were predictable to yield standards within the superior range conferring to Lipinski's rule of five. The number of hydrogen bond donors and hydrogen bond acceptors for DADS found to be 2 and 5 respectively satisfies the Lipinski's rule of five. The values of log P was recognised to be 2.9, which is a pointer of hydrophobic/lipophilic nature of compound and Molar refractivity found to be 81.05 is perceived to be within the appropriate range [76, 77] . Since DADS obeys the Lipinski's rule of five it is confirmed that it is an active potential drug and has drug properties. So DADS is suggested to be used as an antiviral drug to treat certain viral diseases. Molecular docking studies also confirm that DADS is preferable to be used as an antiviral drug ascribed to its good binding affinity towards SARS-CoV-2 and MERS virus proteins. In the present work a complete study on the structural, vibrational, electronic, topology and thermodynamic properties of DADS was carried out with the aid of quantum chemical calculations. The structural optimization of DADS was conceded out by B3LYP method and geometrical parameters are calculated. Intermolecular interaction which confirms biological activity of compound is found from the deviation in bond length of N 22 -H 16 ...O 15 . Presence of intermolecular hydrogen bonding which confirms the nature and properties of biomolecules is also studied by the NBO analysis. Detailed interpretation of vibrational assignments were done with the aid of NCA and the FT-IR, Raman spectra of DADS were recorded and analysed. The frontier orbital gap calculated as 4.9329 eV indicates that DADS is more polarizable and is generally associated with a high chemical reactivity. The charge transfer in molecular orbitals is responsible for the bioactive property for the biomedical compound. The electronic properties were studied theoretically using TD-DFT method and experimentally by observing UV spectrum band where the energy gap calculated from the UV spectrum agrees with the HOMO-LUMO energy gap. Electron distribution and reactive sites on the surface were analysed using ESP, ELF and LOL. HOMA index value confirms the aromatic character of the compound and the difference in HOMA index value in the phenyl ring and pyridine ring is due the substitutions in the place of hydrogen. From the correlation between the Thermodynamical parameters and temperature it is seen that thermodynamic parameters increase with increasing temperature since the molecular vibrational intensities increases with temperature. NCI approach analyses the weak attractive interactions, strong attraction, and steric repulsion existed in the title compound. Molecular docking of DADS is carried out with SARS-CoV-2 and MERS virus proteins affirms that DADS act as a good antiviral agent and further drug likeness studies also supports that DADS can be used as an active drug to treat certain viral diseases including Covid-19 virus disease. 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the study of aromaticity Biological and spectral studies of O-Tolyl Biguanide: Experimental andtheoretical approach Absolute electronegativity and hardness correlated with molecular orbital theory Synthesis, characterization and spectroscopic investigation of N-(2-acetylbenzofuran-3-yl)acrylamide monomer: Molecular structure, HOMO-LUMO study, TD-DFT and MEP analysis Aída Ben Altabe, Ab-initio and DFT calculations on molecular structure, NBO,HOMO-LUMO study and a new vibrational analysis of 4-(Dimethylamino) BenzaldehydeSpectrochim Charge transfer interactions and nonlinear optical properties of push pull chromophore benzaldehyde phenylhydrazone: a vibrational approach The use of global and local molecular parameters forthe analysis of the gas-phase basicity of amines Spectroscopic elucidation (FT-IR, FT-Raman and UV-visible) with NBO,NLO, ELF, LOL, drug likeness and molecular docking analysis on 1-(2-ethylsulfonylethyl)-2-methyl-5-nitro-imidazole: An antiprotozoal agent DFT study of dimers of dimethylnitramine Compound electrostatic potentials and average local ionization energies on the molecular surfaces of some teracyclines Molecular structure and spectroscopic properties of novelmanganese (II) complex with sulfamethazine drug Hardness, softness, and the fukui function in the electronic theory of metals and catalysis Proc New dual descriptor forchemical reactivity Molecular docking studies, charge transfer excitation and wave function analyses (ESP, ELF, LOL) on valacyclovir: A potential antiviral drug Comput Localized-orbital locator (LOL) profiles of chemical bonding molecular structure, ESP, NBO and HOMO-LUMO investigation of 2-methylpyridine 1-oxide: A combined experimental and DFT study Protein structure determination from NMR chemical shifts Proc Synthesis, spectroscopic and computational studies of 2-(thiophen-2-yl)-2, 3-dihydro-1H-perimidine: an enzymes inhibition study NMR characterization of C3H and HCT down-regulated alfalfa lignin Carbon 13 NMR Spectroscopy Fukui function analysis of 5-Methoxy-1H-benzo[d]imidazole-2(3H)-thione by DFT studies Non-covalent interaction via the reduced density gradient: independent atom model vs experimental multipolar electron densities Revealing noncovalent interactions Thermodynamics and Statistical Mechanics, fifthed HOMO-LUMO and docking studies of 2,2-dimethyl-N-(2-pyridinyl)propanamide -a DFT approach IR, 1H NMR and DFT studies of novel bis-Betti base derivatives of 2,6-dihydroxynaphthalene: thermodynamic control of diastereoselectivity and configurational preference Computational assessment on wave function (ELF, LOL) analysis, molecular confirmation and molecular docking explores on 2 PROCHECK: a program to check the stereochemical quality of protein structures Lead-and drug-like compounds: the rule-of-five revolution Prediction of drug-likeness Computational methods for the prediction of druglikeness The authors express their gratitude to Dr. I. Hubert Joe, Associate Professor, Department of Physics, University of Kerala for providing us Gaussian software for Computational works.