Screening of phytochemicals as potent inhibitor of 3-chymotrypsin and papain-like proteases of SARS-CoV2: an in silico approach to combat COVID-19

Abstract

COVID-19 and its causative organism SARS-CoV2 that emerged from Wuhan city, China have paralyzed the world. With no clinically approved drugs, the global health system is struggling to find an effective treatment measure. At this crucial juncture, screening of plant-derived compounds may be an effective strategy to combat COVID-19. The present study investigated the binding affinity of phytocompounds with 3-Chymotrypsin-like (3CLpro) and Papain-like proteases (PLpro) of SARS-CoV2 using in-silico techniques. A total of 32 anti-protease phytocompounds were investigated for the binding affinity to the proteins. Docking was performed in Autodock Vina. Pharmacophore descriptors of best ligands were studied using LigandScout. Molecular dynamics (MD) simulation of apo-protein and ligand-bound complexes was carried out in YASARA software. The druglikeness properties of phytocompounds were studied using ADMETlab. Out of 32 phytochemicals, amentoflavone and gallocatechin gallate showed the best binding affinity to 3CLpro (-9.4 kcal/mol) and PLpro (-8.8 kcal/mol). Phytochemicals such as savinin, theaflavin-3,3-digallate, and kazinol-A also showed strong affinity. MD simulation revealed ligand-induced conformational changes in the protein with decreased surface area and higher stability. The RMSD/F of proteins and ligands showed stability of the protein suggesting the effective binding of the ligand in both the proteins. Both amentoflavone and gallocatechin gallate possess promising druglikeness property. The present study thus suggests that Amentoflavone and Gallocatechin gallate may be potential inhibitors of 3CLpro and PLpro proteins and effective drug candidates for SARS-CoV2. However, the findings of in silico study need to be supported by in vivo studies to establish the exact mode of action.Communicated by Ramaswamy H. Sarma.

Keywords: 3CLpro; PLpro; Phytocompounds; SARS-CoV2; docking.

Figure 1.

Binding energies of anti-protease phytocompounds with 3-chymotrypsin-like and papain-like proteases of SARS-CoV2.

Figure 2.

Binding interactions of SARS-CoV2 3-chymotrypsin-like protease and amentoflavone. (a) Ligand binding sphere and surface view of protein, (b) two-dimensional display of ligand-3CLpro interactions, (c) Ramachandran plot of 3CLpro, (d) H-bond property of binding pocket, (e) hydrophobicity profile of binding pocket, and (f) Ramachandran plot of ligand-interacting amino acid residues.

Figure 3.

Binding interactions of SARS-CoV2 Papain-like protease and gallocatechin gallate. (a) Ligand binding sphere and surface view of PLpro, (b) two-dimensional display of ligand-PLpro interactions, (c) Ramachandran plot of PLpro, (d) H-bond property of binding pocket, (e) hydrophobicity profile of binding pocket, and (f) Ramachandran plot of ligand-interacting amino acid residues.

Figure 4.

Two-dimensional and three-dimensional display of pharmacophore feature of amentoflavone (a and b) and gallocatechin gallate (c and d). Green arrow, H-bond donor (HBD); red arrow, H-bond acceptor (HBA); yellow colour, hydrophobic group (H); blue, aromatic ring (AR); brown color with three spikes, non-ionising group (NI) of the compounds.

Figure 5.

Molecular dynamics simulation of phytocompounds with 3CLpro and PLpro proteins of SARS-CoV2. (a) RMSD of apo- and ligand-bound 3CLpro and PLpro proteins, (b) Rg values, (c) fluctuations in the solvent accessibility surface area, and (d) nature of H-bonding during the period of simulation.

Figure 6.

(a) RMSD of amino acids of apo and ligand-bound 3CLpro, (b) RMSD of amino acids of apo and ligand-bound PLpro protein, (c) RMSD of ligand atoms and, (d) binding energies of protein-ligand complexes during the period of simulation (100 ns).

Figure 7.

Binding interactions between 3CLpro protein and amentoflavone complex at different time intervals of MD simulation (colour representations are same as Figure 2).

Figure 8.

Binding interactions between PLpro protein and gallocatechin gallate complex at different time intervals of MD simulation (colour representations are same as Figure 2).

Figure 9.

Superimpositions of pre-(pink) and post-MD simulations (green) of three-dimensional structures of 3CL-protease and PL-protease of SARS-CoV2 during.

Figure 10.

ADMET properties of the best-binding phytocompounds with 3CL protease and PL protease of SARS-CoV2. HIA, human intestinal absorption; BBB, blood-brain barrier; H-HT, human hepatotoxicity; AMES, Ames mutagenicity, SkinSen, skin sensitization; DILI, drug induced liver injury; blue colored chemicals; PL, protease docked compounds.