An investigation into the identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking study

TLDR

SARS‑CoV‑2 has caused a global pandemic, prompting clinical trials for specific drugs, and inhibition of its main protease is essential to block viral replication, though computational findings require experimental validation. The study aims to identify potential inhibitors of the SARS‑CoV‑2 main protease using blind molecular docking of 33 diverse molecules. A blind docking approach was applied to screen 33 compounds—including natural products, antivirals, antifungals, anti‑nematodes, and anti‑protozoals—against the protease structure PDB 6Y84. All 33 compounds bound the protease active site, with rutin showing the highest inhibition efficiency, followed by ritonavir, emetine, hesperidin, lopinavir, and indinavir, all interacting near catalytic residues HIS41 and CYS145 and surrounded by residues such as MET49, GLY143, HIS163, HIS164, GLU166, PRO168, and GLN189.

Abstract

A new strain of a novel infectious disease affecting millions of people, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been declared as a pandemic by the World Health Organization (WHO). Currently, several clinical trials are underway to identify specific drugs for the treatment of this novel virus. The inhibition of the SARS-CoV-2 main protease is necessary for the blockage of the viral replication. Here, in this study, we have utilized a blind molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 main protease, by screening a total of 33 molecules which includes natural products, anti-virals, anti-fungals, anti-nematodes and anti-protozoals. All the studied molecules could bind to the active site of the SARS-CoV-2 protease (PDB: 6Y84), out of which rutin (a natural compound) has the highest inhibitor efficiency among the 33 molecules studied, followed by ritonavir (control drug), emetine (anti-protozoal), hesperidin (a natural compound), lopinavir (control drug) and indinavir (anti-viral drug). All the molecules, studied out here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease, and the molecules were surrounded by other active site residues like MET49, GLY143, HIS163, HIS164, GLU166, PRO168, and GLN189. As this study is based on molecular docking, hence being particular about the results obtained, requires extensive wet-lab experimentation and clinical trials under in vitro as well as in vivo conditions.