Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19

The importance of the main protease (M-pro) enzyme of SARS-CoV-2 in the digestion of viral polyproteins introduces M-pro as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, molecular dynamics studies, and prediction of ADMET properties of selected potential antiviral molecules. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the tested ligands and further, identification of key amino acid residues within the substrate-binding pocket that can be applied for structure-based drug design. In this regard, we carried out molecular docking studies of chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV), GS441524, arbidol (ARB), and natural product glycyrrhizin (GA) using AutoDock 4.2 tool. To study the drug-receptor complex's stability, selected docking possesses were further subjected to molecular dynamics studies with Schrodinger software. The prediction of ADMET/toxicity properties was carried out on ADMET Prediction (TM). The docking studies suggested a potential role played by CYS145, HIS163, and GLU166 in the interaction of molecules within the active site of COVID-19 M-pro. In the docking studies, RDV and GA exhibited superiority in binding with the crystal structure of M-pro over the other selected molecules in this study. Spatial orientations of the molecules at the active site of M-pro exposed the significance of S1-S4 subsites and surrounding amino acid residues. Among GA and RDV, RDV showed better and stable interactions with the protein, which is the reason for the lesser RMSD values for RDV. Overall, the present in silico study indicated the direction to combat COVID-19 using FDA-approved drugs as promising agents, which do not need much toxicity studies and could also serve as starting points for lead optimization in drug discovery. Graphic abstract

Automated summary

This study focuses on the importance of M-pro enzyme of SARS-CoV-2 as a potential drug target for antiviral drug design. Through molecular docking and dynamics studies, the research identified key amino acid residues and potential antiviral molecules for structure-based drug design. The findings suggest that FDA-approved drugs could be promising agents to combat COVID-19, without requiring extensive toxicity studies, and may serve as starting points for lead optimization in drug discovery.