Molecular docking, validation, dynamics simulations, and pharmacokinetic prediction of natural compounds against the SARS-CoV-2 main-protease

Abstract

The study aims to evaluate the potency of two hundred natural antiviral phytocompounds against the active site of the Severe Acquired Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) Main-Protease (M^pro) using AutoDock 4.2.6. The three- dimensional crystal structure of the M^pro (PDB Id: 6LU7) was retrieved from the Protein Data Bank (PDB), the active site was predicted using MetaPocket 2.0. Food and Drug Administration (FDA) approved viral protease inhibitors were used as standards for comparison of results. The compounds theaflavin-3-3'-digallate, rutin, hypericin, robustaflavone, and (-)-solenolide A with respective binding energy of -12.41 (Ki = 794.96 pM); -11.33 (Ki = 4.98 nM); -11.17 (Ki = 6.54 nM); -10.92 (Ki = 9.85 nM); and -10.82 kcal/mol (Ki = 11.88 nM) were ranked top as Coronavirus Disease - 2019 (COVID-19) M^pro inhibitors. The interacting amino acid residues were visualized using Discovery Studio 3.5 to elucidate the 2-dimensional and 3-dimensional interactions. The study was validated by i) re-docking the N3-peptide inhibitor-M^pro and superimposing them onto co-crystallized complex and ii) docking decoy ligands to M^pro. The ligands that showed low binding energy were further predicted for and pharmacokinetic properties and Lipinski's rule of 5 and the results are tabulated and discussed. Molecular dynamics simulations were performed for 50 ns for those compounds using the Desmond package, Schrödinger to assess the conformational stability and fluctuations of protein-ligand complexes during the simulation. Thus, the natural compounds could act as a lead for the COVID-19 regimen after in-vitro and in- vivo clinical trials.Communicated by Ramaswamy H. Sarma.

Keywords: Antiviral phytocompounds; COVID-19; SARS-CoV-2; decoy ligands; main-protease; molecular dynamics simulations; pharmacokinetic properties.

Graphical abstract

Figure 1.

Work flow of the study.

Figure 2.

Three-dimensional structure of Main-protease (PDB Id: 6LU7).

Figures 3 and 4.

3 D and 2 D interaction of atazanavir with M^pro (−13.24 kcal/mol).

Figures 5 and 6.

3 D and 2 D interaction of theaflavin-3-3’-digallate with M^pro (−12.41 kcal/mol).

Figure 7.

Surface image of theaflavin-3-3’-digallate in the M^pro active site cleft.

Figures 8 and 9.

3 D and 2 D interaction of rutin with M^pro (−11.33 kcal/mol).

Figures 10 and 11.

3 D and 2 D interaction of hypericin with M^pro (−11.17 kcal/mol).

Figure 12.

Two-dimensional LigPlot image of N3-M^pro complex from PDBsum.

Figure 13.

Superimposition of re-docked N3-M^pro (blue) onto co-crystallized complex (red) in the active site using PyMOL (RMSD = 0.625 Å).

Figure 14.

Re-docked N3-M^pro onto co-crystallized complex using LigPlot + v.2.2 showing superimposed amino acids (red circle).

Figure 15.

Molecular dynamics RMSD and RMSF of free M^pro (i, ii); N3-M^pro co-crystallized complex (iii, iv); theaflavin-3-3’-digallte (v, vi); rutin (vii, viii); hypericin (ix, x).

Figure 16.

Protein-ligand contact plots and ligand-protein interaction residues of co-crystallized complex (i, ii); theaflavin-3-3’-digallate (iii, iv); rutin (v, vi); hypericin (vii, viii).