Glide docking uses the hypothesis of a rigid receptor although scaling of van der Waals radii of nonpolar atoms, which decreases penalties for close contacts, can be used to model a slight “give” in the receptor and/or ligand. Docking studies of designed compounds were carried out using grid-based ligand docking with energetics (GLIDE) module version 5.9. Schrödinger, LLC, New York, NY, 2013. The software package running on multiprocessor Linux PC. GLIDE has previously been validated and applied successfully to predict the binding orientation of many ligands.
Data sources
In this study, a dataset of active phytochemicals were obtained from FDA and Indian Medicinal Plants, Phytochemistry, and Therapeutics and pubchem database.
Protein structure preparation
The X-ray crystal structures of COVID–19 major protease (PDB: 6LU7) (Prajapat et al., 2020) retrieved from the RCSB Protein Data Bank (https://www.rcsb.org/structure/6LU7) PDB is an archive for the crystal structures of biological macromolecules, worldwide (Jayaprakasha et al., 2002). Water molecules of crystallization were removed from the complex, and the protein was optimized for docking using the protein grounding and refinement utility provided by Schrödinger LLC.
Determination of Active Sites
The amino acids in the active site of a protein were determined using the Computed Atlas for Surface Topography of Proteins (CASTp) (http://sts.bioe.uic.edu/castp/index.html?201l) and Biovia Discovery Studio 4.5. The determination of the amino acids in the active site was used to analyze the Grid box and docking evaluation results. Discovery Studio is an offline life sciences software that provides tools for protein, ligand, and pharmacophore modelling (Gopal Samy and Xavier, 2015).
Target protein and ligand preparation
The structures of energetic constituents of T. Grandis were constructed by means of the splinter dictionary of Maestro 9.3 (Schrodinger, LLC) using the optimized potentials for liquid simulations-all atom force field with the steepest descent followed by curtailed Newton conjugate gradient protocol. The crystal structure of the above-mentioned targets was downloaded from the Protein Data Bank (PDB) and Pubchem databases. The selected protein targets were prepared for docking studies using the protein preparation wizard module in Schrodinger program (Maestro 9.3.). The preparation includes force field parameters assignment, energy minimization and H-bond assignment. The energy minimized models of ligands obtained after molecular modeling studies were then prepared using ligprep module. Geometries of ligands was optimized using OPLS–2005 force field and ionization generates possible states at target pH 7.0 ± 2.0
Receptor Grid preparation and Molecular Docking
All docking calculations were performed using the “extra precision” mode of GLIDE program. A receptor grid that defines the specific area of the protein to which the interaction of ligand has to be tested was defined by the receptor grid generation module. The position of the co- crystal ligand defines the Centre of the grid For the binding site, an assortment of energy grids was premeditated and stored, is distinct in terms of two concentric cubes: The bounding box, which must contain the center of any satisfactory ligand pose, and the enclosing box, which must contain all ligand atoms of an satisfactory pose, with a root mean square deviation of <0.5 Å and a maximum atomic displacement of <1.3 Å were eliminated as unneeded to increase assortment in the retained ligand poses. The scale factor for van der Waals radii was applied to those atoms with absolute partial charges ≤0.15 (scale factor of 0.8) and 0.25 (scale factor of 1.0) electrons for ligand and protein, respectively. Energy minimization protocol includes dielectric constant of 4.0 and 1000 steps of conjugate gradient. Upon end of each docking calculation, for the most part, 100 poses per ligand were generated. The most excellent docked structure be preferred using a GLIDE score (G-score) function (Amudha and Rani, 2016; Parasuraman et al., 2014)
Glide Score = 0.065*vdW + 0.130*Coul + Lipo + Hbond + Metal + BuryP + RotB + Site
Analysis and visualization
Visual analysis of the docking site was performed using Pymol version 2.3.4 and the results were validated using Schrodinger program (Maestro 9.3.)
ADME analysis
On the basis of canonical SMILES of the selected ligands obtained from pubchem, ADME properties of the studied compound were calculated using online Swiss ADME program. The major parameters for ADME associated properties such as Lipinski’s rule of five, the solubility of the drug, pharmacokinetic properties and drug likeliness were considered. The values of the observe properties are presented in Table 3.