Finding potent inhibitors against SARS-CoV-2 main protease through virtual screening, ADMET, and molecular dynamics simulation studies

Abstract

Currently, no antiviral drug or vaccine is available to treat COVID-19 caused by SARS-CoV-2. This underscores an urgent need for developing a drug against SARS-CoV-2. The main protease (3CL^pro) of SARS-CoV-2 is considered an essential protein for maintaining the viral life cycle and, therefore, a potential target for drug development. In a recent study, 1000 potential ligands were identified for 3CL^pro by screening 1.3 billion compounds from the ZINC15 library. In the current study, we have further screened these 1000 compounds using structure-based virtual screening utilizing the Schrödinger suite and identified nine compounds having a docking score of ∼ -11.0 kcal/mol or less. The top 5 hits display good pharmacological profiles revealing better absorption, proper permeability across the membrane, uniform distribution, and non-toxic. The molecular docking study is further complemented by molecular dynamics simulations of the top 5 docked complexes. The binding free energy analyses via the molecular mechanics generalized Born surface area (MM/GBSA) scheme reveals that ZINC000452260308 is the most potent (ΔG_bind = -14.31 kcal/mol) inhibitor. The intermolecular van der Waals interactions mainly drive the 3CL^pro-ligand association. This new compound may have great potential as a lead molecule to develop a new antiviral drug to fight against COVID-19.Communicated by Ramaswamy H. Sarma.