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. 2021 Jul;13(3):359-369.
doi: 10.1016/j.chmed.2021.06.002. Epub 2021 Jun 24.

Dual inhibition of COVID-19 spike glycoprotein and main protease 3CLpro by Withanone from Withania somnifera

Vishal Shivalingappa Patil  1 , Vrushabh B Hupparage  1 , Ajay P Malgi  1 , Sanjay H Deshpande  2 , Sathgowda A Patil  1 , Shamanand P Mallapur  1
Affiliations

Dual inhibition of COVID-19 spike glycoprotein and main protease 3CLpro by Withanone from Withania somnifera

Vishal Shivalingappa Patil et al. Chin Herb Med. 2021 Jul.

Abstract

Objective: To identify the safe and effective natural inhibitors of spike glycoprotein and main protease 3CLpro using potential natural antiviral compounds which are studied under various animal models and viral cell lines.

Methods: First, compounds were retrieved from the PubChem database and predicted for their druggability using the MolSoft web server, and compounds having drug-like property were predicted for major adverse drug reactions like cardiotoxicity, hepatotoxicity, arrhythmia, myocardial infarction, and nephrotoxicity using ADVERpred. Docking of nontoxic antiviral compounds with spike glycoprotein and main protease 3CLpro was performed using AutoDock vina by PyRx 0.8 version. The stability of compound-protein interactions was checked by molecular dynamic (MD) simulation using Schrodinger Desmond software.

Results: Based on the druggable and nontoxic profile, nine compounds were selected. Among them, Withanone from Withania somnifera showed the highest binding affinity and best fit at active sites 1 of spike glycoprotein (glycosylation site) and main protease 3CLpro via interacting with active site amino acid residues before and after MD simulation at 50 ns. Withanone, which may reduce the glycosylation of SARS-CoV-2 via interacting with Asn343 and inhibit viral replication.

Conclusion: The current study reports Withanone as a non-toxic antiviral against SARS-CoV-2 and serve as a potential lead hit for further experimental validation.

Keywords: COVID-19; SARS-CoV-2; Withania somnifera (Linn.) Dunal; Withanone; antiviral; docking; dynamics; main protease 3CLpro; spike glycoprotein.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Amino acid distribution and quality factor of (A) Spike glycoprotein (PDB ID: 6LZG) and (B) main protease (PDB ID: 7BUY).
Fig. 2
Fig. 2
Interaction of Withanone with Spike glycoprotein. (A) 2D representation; (B) Withanone fit at glycosylation site; (C) 3D representation; (D) Withanone within binding pocket and (E) active site 1 region.
Fig. 3
Fig. 3
Interaction of Withanone with main protease 3CLpro. (A) 2D representation; (B) Withanone fit ligand binding site; (C) 3D representation; (D) Withanone within binding pocket and E) active site 2 region.
Fig. 4
Fig. 4
Orientation of Withanone in glycosylation site of spike glycoprotein (A) and ligand state alignment (B) pre-simulation (violet) and post-simulation (green).
Fig. 5
Fig. 5
Orientation of Withanone in binding site of Main protease 3CLpro (A) and ligand state alignment (B) pre-simulation (violet) and post-simulation (green).
Fig. 6
Fig. 6
Molecular dynamic simulation of Withanone - spike glycoprotein complex at 50 ns. RMSD (A), contacts (B), RMSF with contacts (C), and hydrogen, hydrophobic, ionic bonds, and water bridges (D).
Fig. 7
Fig. 7
Molecular dynamic simulation of Withanone – Main protease 3CLpro complex at 50 ns. RMSD (A), contacts (B), RMSF with contacts (C), and hydrogen, hydrophobic, ionic bonds, and water bridges (D).
See this image and copyright information in PMC

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