Therapeutic options of covid-19 management: computational approach targeting main protease (Mpro)

Abstract

Main protease (Mpro) enzyme of SARS-CoV-2 is involved in the digestion of viral polyproteins and considered as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, density functional theory (DFT) studies, prediction of ADMET properties of selected potential antiviral molecules, study the efficacy of selected hits on predicted mutated Main protease (Mpro) enzyme, and the drug-drug interaction of potential hits. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the ligands and further, identification of key amino acid residues within the substratebinding pocket that can be applied for structure-based drug design.Molecular docking of FDA approved drugs (1167) screened through stringent parameters and our formula for preference index identified tadalafil as competitive inhibitor of proteolytic function of main protease.In the docking studies, tadalafil exhibited superiority in binding with the crystal structure of Mproover the other selected molecules in this study, suggestedby the crucial roles of CYS145, HIS163, and GLU166 in the interaction within the activesite of COVID-19 Mpro. Further, the binding affinity in the predicted mutated structuresof main protease was also found to be higher than wild type suggesting its broad use. The thermodynamic properties and molecular orbital properties investigated for this compound followed the required drug like property of a probable drug. The original library of FDA compounds was docked with human cytochrome P450 3A4 and the inhibitory activity of drospirenone suggested its impeding caliber in clearance of tadalafil. Overall, the present in silico study indicated the direction to combat COVID19 using FDA-approved drugs as therapeutic alternative for viral inhibition or symptom management, which do not need much toxicity studies and could also serve as starting points for lead optimization in drug discovery. Keywords: ADMET, COVID-19, drug discovery, Mpro, molecular docking, therapeutic alternative