Crystal structure, DFT studies, Hirshfeld surface and energy framework analysis of 4-(5-nitro-thiophen-2-yl)-pyrrolo [1, 2-a] quinoxaline: A potential SARS-CoV-2 main protease inhibitor

Abstract

The title compound 4-(5-nitro-thiophen-2-yl)-pyrrolo[1,2-a] quinoxaline (5NO₂TAAPP) was obtained by a straightforward catalyst-free reaction of 5-nitro-2- thiophene carboxaldehyde and 1-(2-aminophenyl) pyrrole in methanol and was structurally characterized by FT IR, UV–Vis, NMR spectroscopic techniques and elemental analysis. The structure of the compound has been confirmed by the single-crystal X-ray diffraction technique. The compound crystallizes in a monoclinic crystal system with space group P2₁/c. Unit cell dimensions: a = 12.2009(17) A⁰, b = 8.3544(9) A⁰, c = 13.9179(17) A⁰ and β = 104.980(5) A⁰. Hirshfeld surface analysis was carried out to understand the different intermolecular interactions. The two-dimensional fingerprint plot revealed the most prominent interactions in the compound. Theoretical calculations were executed using Density functional theory (DFT) by Gaussian09 software to develop optimized geometry and frontier molecular orbital analysis. Molecular docking studies revealed that the title compound is a potent inhibitor of Main protease 3CL^pro with PDB ID: 6LU7, the viral protease which is responsible for the new Corona Virus Disease (COVID-19).

1. Introduction

SARS-CoV-2 outbreak poses a serious threat to humanity all over the world today. It was declared as a pandemic by World Health Organization on 11 March 2020 [1]. Currently, there are no effective drugs developed for the treatment of this disease. Researches are going on for developing vaccines, druggable molecules, monoclonal antibodies, and cell-based therapies [2]. The chymotrypsin-like cysteine protease also known as Main protease ³CLpro plays an important role in viral replication of SARS-CoV-2 [3]. ³CLpro is the key target in anti-COVID-19 drug design due to its non-similarity with human proteins [3,4].

Compounds with quinoxaline ring systems are extensively studied for the last two decades due to their wide range of biological properties. Several quinoxaline derivatives have been reported to possess remarkable pharmacological properties which fight against several diseases with few side effects. They have been described as anti-inflammatory [5], antimalarial [6], antidepressants [7], antiviral [8], antimicrobial [9,10] as antifungal and antibacterial agents.

Pyrrolo [1, 2-a] quinoxalines, an important heterocyclic compound bearing quinoxaline moiety is characterized by a broad range of biological properties [11]. Derivatives of these tricyclic systems have received a great deal of attention for their miscellaneous use in the medicinal field as antileukemic [12], anti-tuberculosis [13], antimalarial [14], anti–Leishmania [15] antidiabetic [16,17] and antibacterial [18] agents. Also, well-established evidence showed that several pyrrolo [1,2-a] quinoxaline-based compounds act as inhibitors against human protein kinase CK2, AKT kinase [19]. Furthermore, suitably functionalized quinoxaline derivatives can act as promising antiviral drugs [8]. At present, research on the synthesis, characterization, and development of new candidates which can effectively bind the Covid 19 Main protease is flying up [4]. In this context, we have been enthused to screen, in silico, the interaction between the main protease (6LU7) active site with a pyrrolo [1, 2-a] quinoxaline-based compound.

Methods to synthesize pyrrolo [1,2-a] quinoxalines often involve the use of functionalized aniline precursors [20], transition metal catalysts [21], [22], [23], and harsh reaction conditions. We aimed to develop a simple method that avoids the use of expensive transition metal catalysts and dangerous oxidizers. In this paper, we have described the synthesis of a new pyrrolo [1, 2-a] quinoxaline compound, 4-(5-nitro-thiophen-2-yl)-pyrrolo[1,2-a] quinoxaline (5NO₂TAAPP) in good yield through the simple coupling of 1-(2- aminophenyl) pyrrole and 5-nitro-2- thiophene carboxaldehyde. We also report the single-crystal X-ray structure, spectral characterization, Hirshfeld Surface analysis, and from the docking studies, predicted the binding affinity of this compound to the active site of 6LU7.

2. Experimental

2.1. General characterization techniques

1-(2- aminophenyl) pyrrole and 5-nitro-2- thiophene carboxaldehyde were purchased from Sigma Aldrich. All the chemicals and reagents were of analytical grade and used without further purification. Electronic spectra of the compound were recorded in DMF on a Thermo electron Nicolet evolution 300 UV–Vis spectrophotometer. FT-IR spectra of the compound were recorded as KBr pellets with a JASCO-8000 FT-IR spectrophotometer in the 400–4000 cm⁻¹ range. Elemental analyzes of the compound were done using an Elementar Vario EL III CHN analyzer at Sophisticated Test and Instrumentation Centre (SAIF), Cochin University of Science and Technology, Kochi, India. ¹H and ¹³C NMR spectra were recorded in CDCl₃ on a Burker Advance DRX 300 FT-NMR spectrometer with TMS as the internal standard.

2.2. Synthesis of 5NO₂TAAPP

A methanolic solution (10 mL) of 5-nitro-2- thiophene carboxaldehyde (2 mmol) and 1-(2-amino phenyl) pyrrole (2 mmol) was refluxed in an oil bath at 60 °C for 12 h. On completion of the reaction as observed using TLC (20:80; Ethyl acetate: Hexane), the solvent was evaporated. The crystalline precipitate formed was collected through filtration using a vacuum pump, washed with cold methanol, dried, and recrystallized from methanol. The light-yellow single crystals were collected. The yield and melting point of the product were determined. Yield 80%; m. p 125–127 °C; IR (KBr, cm⁻¹): 3070(CH), 1607(C=N), 1495(NO₂); UV Vis (λ, nm): 228, 315; ¹H NMR (400 MHz, DMSO‑d₆, δ ppm): 7.9(1H, J = 4.4 Hz, d), 7.4(1H, J = 12 Hz, d), 7.1(1H, J = 4 Hz, d), 6.7–6.9(4H, m), 6.2(1H, J = 3.2 Hz, t), 6.01(1H, J = 2.8 Hz, d); ¹³C NMR (DMSO‑d₆, δ ppm): 157.9, 149.9, 145.1, 134.8, 130.4, 126.8, 125.5, 125.2, 124.6, 119.4, 116.2, 115.8, 115.2, 110.7, 106.1; Anal. Calcd. For: C₁₅H₉N₃O₂S (295.04) C, 61.01; H, 3.07; N, 14.23; S, 10.86, Found: C, 60.80; H, 3.12; N, 14.16; S, 10.52.

2.3. Crystal structure determination and refinement

Single crystal of the compound 5NO₂TAAPP, suitable for X-ray structure analysis was obtained by slow evaporation at room temperature from its methanolic solution over 24 h. The single-crystal X-ray diffraction studies were carried out using a Bruker AXS Kappa Apex 2 CCD diffractometer, with graphite monochromator Mo Kα radiation (k = 0.71073 Å). The unit cell dimensions and intensity data were recorded at 296 K. The structure was solved with the direct method using SIR 92 [24] and refinement was carried out by full-matrix least-squares on F2 using SHELXL-97 [25]. The program SAINT/XPREF was used for data reduction and APEX2/ SAINT for cell refinement [26]. Software used for computing molecular graphics ORTEP 3 [27] and Mercury [28]. Software used to prepare material for publication SHELXL-97.

2.4. DFT and Hirshfeld surface analysis

The density functional theory calculations were performed with Gaussian 09 package [29] with the B3LYP exchange-correlation functional and the 6–31 G (d, p) basis set. For the 5NO₂TAAPP optimized structure, Frontier molecular orbitals (HOMO, LUMO) and Mulliken atomic charges were generated using GaussView05 [30]. Hirshfeld surfaces were created using the Crystal Explorer 17 program [31]. The energy framework and interaction energies of the 5NO₂TAAPP molecule were calculated using the TONTO program [32], which is inherent in Crystal Explorer 17 software. The initial geometries were taken from the X-ray data CIF file of 5NO₂TAAPP and used as input files for DFT and Hirshfeld surface analysis.

2.5. Molecular docking

The structure of 3CL^pro protein having PDB ID: 6LU7 was retrieved from RCSB Protein Data Bank [33]. An online server, Expasy protparam which provides all information regarding the protein was used for its characterization. Molecular docking was performed using Autodock 4.2.6 [34]. Both protein and ligand were prepared in pdbqt format. Polar hydrogens and Gasteiger charges were added to the receptor. Grid centerd at −19.173, 20.969, 68.039 A⁰ along x, y, z axes was prepared with 60 Χ 60 Χ 60 A^{0 3} with spacing 0.375 A⁰. The genetic algorithm was employed as a search parameter with 50 runs, 300 population size and 27,000 number of generations, respectively.

3. Results and discussion

3.1. Characterization

The title compound 4-(5-nitro-thiophen-2-yl)-pyrrolo [1, 2-a] quinoxaline (5NO₂TAAPP) was synthesized (Scheme 1 ) and characterized. The synthesized compound was crystalline, non-hygroscopic, insoluble in water but soluble in methanol, DMF and DMSO. The compound was characterized by elemental analysis, IR, UV-Visible spectra and NMR analysis. UV-Visible, IR and NMR (¹H and ¹³C) spectra of the title compound are shown in Figs. S1, S2, S3, S4, respectively in the supporting information file.

Scheme 1.

Synthesis of 5NO₂TAAPP

3.2. Crystal structure of 5NO₂TAAPP

The compound could be crystallized from the slow evaporation of its methanolic solution at room temperature. ORTEP diagram of the compound 5NO₂TAAPP with atom numbering scheme is given in Fig. 1 (a). Crystal data and refinement parameters of the compound are given in Table 1 . X-ray crystallographic analysis revealed that the compound crystallizes in a monoclinic crystal system with space group P2₁/c. Unit cell dimensions of the crystal are a = 12.2009(17) Aº, b = 8.3544(9) Aº, c = 13.9179(17) Aº and β = 104.980(5)º. Bond lengths and bond angles obtained from crystal data are summarized in Table 2 .

Fig. 1.

(a) ORTEP diagram of the compound with thermal ellipsoids drawn at 50% probability level (b) The optimized structure of the compound

Table 1.

Crystal data and details of the structure refinement for the title compound.

Parameters

Compound

CCDC number Empirical formula Formula weight Temperature (K) Crystal system Space group a (Å) b (Å) c (Å) Volume (Å3) Z Calculated density (mg/cm3) μ (mm−1) F(000) Crystal size (mm3) Θ range for data collection (°) Index ranges T min, T max Reflections collected/unique Completeness to theta Data/restraints/parameters Goodness-of-fit on F2 Final R indexes [I ≥ 2σ (I)] Final R indexes [all data] Largest diff. peak/hole (e Å−3)

2,093,318 C15H9N3O2S 295.32 296(2) Monoclinic P 21/c 12.2009(17) 8.3544(9) 13.9179(17) 1370.5(3) 4 1.431 0.244 608 0.300 × 0.200 × 0.200 1.728 to 28.420 deg −16<=h<=11, −10<=k<=10,18<=l<=18 0.931,0.953 11,100 / 3405 [R (int) = 0.0335] 25.242,99.9% 3405 / 0 / 190 1.130 R1 = 0.0576, wR2 = 0.1683 R1 = 0.0855, wR2 = 0.1924 0.631 and −0.360

Table 2.

Selected bond lengths (Å) and angles (°) of the crystal structure of the compound.

Bond	Length (Aº)	Bond	Angle (o)
C(1)-S(1)	1.701(3)	N(3)-C(5)-C(4)	108.88(17)
C(4)-C(5)	1.502(3)	N(3)-C(5)-C(6)	108.40(17)
C(4)-S(1)	1.711(2)	C(6)-C(5)-C(4)	111.32(18)
C(5)-N(3)	1.474(3)	C(5)-C(4)-S(1)	120.24(16)
C(6)-N(2)	1.369(3)	C(3)-C(4)-S(1)	112.24(19)
C(9)-N(2)	1.375(3)	C(14)-N(3)-C(5)	116.96(17)
C(14)-N(3)	1.398(3)	C(6)-N(2)-C(15)	122.75(19)
C(15)-N(2)	1.406(3)	C(1)-S(1)-C(4)	89.55(13)
N(1)-O(1)	1.221(4)	O(1)-N(1)-C(1)	117.2(3)
N(1)-O(2)	1.217(4)	O(2)-N(1)-C(1)	118.5(4)

In the crystal structure of the compound, all C—C and C—H bond lengths in the benzene ring are in the normal range and bond angles are approximately 120º. The bond lengths and bond angles in the pyrrole and thiophene ring are comparable to other previously reported crystal structures [35]. The angle between the benzene ring and quinoxaline ring C(13)-C(14)-N(3) and C(10)-C(15)-N(2) are 120.6º and 122.7º, respectively. The thiophene ring joined to the quinoxaline ring through the bonds N(3)-C(5)-C(4), C(6)-C(5)-C(4) at an angle of 108.88º, 111.32º, respectively. The torsion angle between the quinoxaline ring and the thiophene ring is −25.3º and −85.1º for the atoms S(1)-C(4)-C(5)-N(3)and C(3)-C(4)-C(5)-C(6), respectively. CCDC deposition number 2,093,318 contains supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

3.3. Geometry optimization, frontier molecular orbitals and mulliken charges distribution

The optimized geometry of the compound is given in Fig. 1(b). Frontier molecular orbital analysis was carried out which provide an insight into its biological potential and chemical reactivity [36,37]. The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies were calculated to be E_HOMO = −6.0504 eV and E_LUMO = −3.2446 eV. The HOMO – LUMO energy gap is 2.8058 eV. By using frontier molecular orbital energy values, the global reactivity descriptors such as hardness (η), chemical potential (μ), softness (S), electronegativity (χ) and electrophilicity index (ω) have been defined [38, 39]. The frontier molecular orbital and their energy gap for the compound is shown in Fig. 2 . Table 3 lists the energy gap and the other global reactivity descriptors for the title compound.

Fig. 2.

HOMO-LUMO and energy gap of the title compound

Table 3.

HOMO –LUMO and global reactivity descriptors of the title compound.

Parameter	Value
EHOMO ELUMO Energy gap (∆E) Ionization potential (I) Electron Affinity (A) Chemical Hardness (η) Global softness (σ) Eletronegativity (X) Chemical potential (μ) Eletrophilicity (ω)	−6.0504 (eV) −3.2446 (eV) 2.8058 (eV) 6.0504 (eV) 3.2446 (eV) 1.4029 (eV) 0.3564 (eV−1) 4.6475 (eV) −4.6475 (eV) 7.698 (eV)

Mulliken charge distribution within the molecule is very significant because it affects the overall stability, reactivity, electronic structure and more properties of the molecular system [40]. The net atomic charges 5NO₂TAAPP molecule obtained by using Mulliken population analysis, are plotted in Fig. 3 . The result indicates that the S atom has the highest positive charge, with the corresponding value of charge +0.599. The two nitrogen atoms in the quinoxaline ring have the highest electronegativity and the lowest net atomic charge values (−0.848 e and −0.477 e). Therefore, it is anticipated that the quinoxaline ring as a whole or the individual nitrogen atoms within the ring can interact through hydrogen bonds or other intermolecular forces with the suitably positioned amino acid residue in the target protein. In addition, the carbon atoms in the thiophene ring (−0.321, −0.039, −0.074, −0.079 e) and oxygen atoms of the nitro group (−0.302, −0.295 e) also have relatively low atomic charges, may also be involved in prolific binding interactions with the enzymes.

Fig. 3.

Mulliken charge distribution for the optimized compound

3.4. Hirshfeld surface analysis

Hirshfeld surface analysis enables us to understand the packing modes, the surface of the molecular system and intermolecular interactions in crystals. Hirshfeld surface volume and surface area of the compound are 335.91Aº³ and 312.47 Aº², respectively. The globularity and the asphericity for the shape are 0.748 and 0.213, respectively. In the Hirshfeld surface mapped over normalized contact distance d_norm (Fig. 4 ), the white surface area indicates the contact with distances equal to the sum of van der Waals radii, and the red and blue colours indicate the distances shorter (in close contact) or longer (distinct contact) than the van der Waals radii, respectively [41].

Fig. 4.

Three-dimensional Hirshfeld surface of the title compound plotted over d_norm in the range -0.1039 to 1.4949 a. u.

The 2D fingerprint plot permit us to calculate the percentage contribution of each type of contacts for the total Hirshfeld surface area. The H . . . H contacts are responsible for the largest contribution (30.6%) to the Hirshfeld surface. Beside these contacts, H. . .O/O. . .H (24.8%), H . . . C/C . . . H (14.4%), H. . .S/S. . .H (7.3%), H . . . N/N . . .H (5.6%), C. . .C (5.5%), N. . .C/C. . .N (4.6%) and S. . .C/C. . .S (3.1%) interactions contribute considerably to the total Hirshfed surface area. The 2D fingerprint plot for all major contacts are depicted in Fig. 5 . The contributions of other contacts are only minor and add to N . . .N (0.1%), S. . .O/O. . .S (0.1%) and S. . .N/N. . .S(0.1%).

Fig. 5.

2D fingerprint plots for all major contacts on Hirshfeld surface. di and de denote the closest internal and external distances in A° from a point on the surface.

Hirshfeld surface plotted over shape index, curvedness and electrostatic potential map (Fig. 6 .) give more details about the shape and molecular packing in crystals. The shape index map (Fig. 6a.) of the title compound was generated in the range of −1 to 1 Aº. The surface around the acceptor atoms are indicated by the blue colour regions and the surface around the donor atoms are indicated by red colour regions in the shape index map. The curvedness map (Fig. 6b.) of the title compound was generated in the range −4 to 4 Aº. The large green regions indicate a planar surface area, while the blue regions reveal the areas of curvature. The presence of π-π stacking interactions is also evident as the flat regions around the thiophene and benzene ring on the Hirshfeld surface plotted over curvedness. In the electrostatic potential map (Fig. 6c.) over the Hirshfeld surface, the electropositive regions (around hydrogen bond donor) are indicated by blue colour; whereas red colour regions are electronegative regions (around hydrogen bond acceptor) [42].

Fig. 6.

Hirshfeld surface mapped over (a) shape index (b) curvedness (c) electrostatic potential

3.5. Energy framework analysis

The intermolecular interaction energies for the title compound was calculated using CE-B3LYP/6–31 G(d, p) energy model available in crystal explorer with scale factors k_ ele = 1.057, k_ pol = 0.740, k_ disp = 0.871, k_ rep = 0.618, respectively [31]. The different interaction energies, coulombic interaction energy (red), dispersion energy (green), total interaction energy (blue) of the compound are depicted in Fig. 7 . The magnitude of the interaction energy is proportional to the radii of the corresponding cylinder. Table 4 list the result of different interaction energies of the title compound, rotational symmetry operations to the reference molecule (Symop), the centroid to centroid distance between the reference molecule and the interacting molecule (R) and the number of pairs of the interacting molecule to the reference molecule (N).

Fig. 7.

Graphical representation of electrostatic interactions (a) coulomb interaction energy (b) dispersion energy (c) total energy of the title compound

Table 4.

Different interaction energies of compound in KJ/mol.

N	Symop	R (A0)	Eele	Epol	Edis	E rep	Etot
1 2 2 2 1 2 1 2 1 1	-x, -y, -z x,-y + 1/2, z + 1/2 x, y, z -x,y + 1/2,-z + 1/2 -x, -y, -z -x,y + 1/2,-z + 1/2 -x, -y, -z x,-y + 1/2, z + 1/2 -x, -y, -z -x, -y, -z	13.42 12.65 12.20 13.80 7.21 4.29 7.20 7.43 11.56 9.76	2.1 −15.6 5.4 0.5 −12.4 −8.7 1.0 −6.1 −7.9 −3.3	−0.5 −3.7 −2.4 −0.2 −2.9 −4.0 −4.0 −2.1 −2.2 −0.3	−3.1 −8.3 −10.1 −2.0 −15.8 −71.2 −36.7 −18.8 −9.6 −3.5	0.0 5.3 5.7 0.0 5.3 34.5 20.5 9.8 1.5 0.1	−0.9 −21.4 −0.6 −1.4 −24.5 −47.6 −18.0 −16.7 −16.9 −6.7

The calculated electrostatic, polarization, dispersion, repulsion energies are −45.0 KJ/mol, −22.3 KJ/mol, −179.1 KJ/mol and 82.7 KJ/mol, respectively. The calculated total energy of the molecule is −154.7 KJ/mol. The result revealed that dispersion energy is predominant over the other interaction energies and have a key role in the total forces in the crystal packing.

3.6. Docking analysis

The purpose of this docking analysis was to assess the binding affinity of the amino acids within the 3CL^pro _.active site to the target ligand 5NO₂TAAPP. The Auto Dock tool was used to perform the docking of the ligand into the catalytic binding site of SARS-CoV-2 3CL^pro with PDB ID: 6LU7 (Fig. 8 ). The selected protein was characterized by primary and secondary structure analysis as shown in Table 5 .

Fig. 8.

The pictorial representation of the compound 5NO₂TAAPP binded inside the pocket of SARS-CoV-2 main protease 3CL^pro

Table 5.

Characterization of protein.

Properties	Values
molecular weight energy Number of amino acids Theoretical pI Instability index Aliphatic index GRAVY Resolution	333,797.64 KDa −16,473.465 kJ mol−1 306 5.95 27.65 82.12 −0.019 2.16 Å

The isoelectric point (pI value) 5.95 indicates that the protein is slightly acidic. The relative volume of a protein occupied by its aliphatic side chains is termed as the aliphatic index (AI). The aliphatic index plays role in protein thermal stability. A high aliphatic index specifies that the protein is thermally stable over a wide temperature range. Aliphatic index in the range of 66.5 to 84.33 indicate high thermal stability and hydrophobicity of protein, which help them for biological membrane perturbation [43]. The Grand average of hydropathy (GRAVY) value is a measure of the hydrophilic nature of protein [44]. The value obtained for GRAVY is −0.019, which is close to zero, indicate the hydrophobic nature of the protein. The instability index is an assessment of the stability of a protein experimentally. A protein whose instability index is smaller than 40 is predicted as stable [45]. These results indicated that 6LU7 is a stable, hydrophobic protein.

The binding affinity of the inhibitor (ligand or drug) is an important parameter, which determines the strength of its binding interaction with the target protein or the biomolecule. These interactions can be of many kinds such as hydrogen bonding, electrostatic interactions, hydrophobic and van der Waals forces. The 2D interaction diagram of the compound with the target 6LU7 is shown in Fig. 9 . Compound forms two hydrogen bonds with GLY 143 and CYS 145 through an oxygen atom of the nitro group; van der Waals interactions with GLU 166, HIS 164, GLN 189, ASP 187, ARG 188, PRO 52, TYR 54, HIS 41, SER 144, ASN 142; π-sulphur interaction by Sulphur atom of CYS 44 with the π electron cloud of benzene ring; and a π-donor hydrogen bond interaction with the –SH group of CYS 145. MET 165 and MET 49 form π-alkyl bonds with the compound.

Fig. 9.

Interaction of 5NO₂TAAPP with SARS-CoV-2 main protease.

The binding affinity of a ligand with a protein is measured in terms of binding energy. The negative value of binding energy indicates a release of energy while forming a protein−ligand docked complex, which imparts stability. The more negative the binding energy, the higher will be the stability and binding affinity [46]. The binding energy obtained for the compound 5NO₂TAAPP with 6LU7 is −7.95 Kcal mol⁻¹. Hydroxychloroquine and remdesivir, which were approved drugs as inhibitors to SARS- CoV-2 having binding affinity values −6.06 and −4.96 Kcal mol⁻¹, respectively [47]. In general, molecular docking results reveals that there should be effective hydrogen bonding and other hydrophobic interactions between the compound and the target protein. These interactions together with the predicted binding affinity, indicating that the compound 5NO₂TAAPP should show significant SARS-Cov-2 inhibitory activity.

4. Conclusion

The new biologically active compound, 4-(5-nitro-thiophen-2-yl)-pyrrolo[1,2-a] quinoxaline (5NO₂TAAPP) was synthesized and structurally characterized by FT IR, UV–Vis, NMR and elemental analysis techniques. Single crystal X-ray diffraction analysis was used to confirm the three-dimensional conformation of the compound. Hirshfeld surface analysis revealed the important intermolecular interactions and contacts within the crystal structure. Using DFT calculations, its molecular structure was optimized, frontier molecular orbitals were deduced. Molecular docking experiments disclosed that the compound formed important binding interactions with the amino acid residues within the active site of 3CL^pro, the main protease of SARS-CoV-2. Hydrogen bonding and many other hydrophobic interactions are responsible for the binding affinity of the compound with the target protein. The result revealed that the studied compound has a comparable binding affinity for 3CL^pro to that of approved drugs for COVID-19 such as remdesivir and favipiravir. This suggests that the compound can be chosen for further studies as a potential therapeutic candidate for COVID-19.

CRediT authorship contribution statement

K.M. Divya: Writing – original draft, Formal analysis, Visualization. D.P. Savitha: Formal analysis, Writing – review & editing. G. Anjali Krishna: Formal analysis, Visualization. T.M. Dhanya: Formal analysis. P.V. Mohanan: Project administration, Writing – review & editing.

Declaration of Competing Interest

The authors have declared no conflicts of interest.