Structure-based virtual screening to discover potential lead molecules for the SARS-CoV-2 main protease.

The COVID-19 disease is caused by a new strain of coronaviruses family (SARS-CoV-2), and it has affected at present millions of people all over the world. The indispensable role of main protease (Mpro) in viral replication and gene expression makes this enzyme an attractive drug target. Therefore, inhibition of SARS-CoV-2 Mpro as a proposition to halt the virus ingression is being pursued by scientists globally. Here we carried out a study with two objectives, the first being to perform comparative protein sequence and 3D structural analysis to understand the effect of 12 point mutations on the active site. Among these, two mutations, viz., Ser46, and Phe134, were found to cause a significant change at the active sites of SARS-CoV-2. The Ser46 mutation present at the entrance of the S5 sub-pocket of SARS-CoV-2 increases the contribution of other two hydrophilic residues, while the Phe143 mutation is present in the catalytic cysteine loop, can cause an increase in catalytic efficiency of Mpro by facilitating fast proton transfer from Cys145 to His41 residue. It was observed that active site remained conserved among Mpro of both SARS-CoVs, except the entrance of S5 sub-pocket, suggesting sustenance of substrate specificity. The second objective was to screen the inhibitory effects of three different datasets (natural products, coronaviruses main protease inhibitors, and FDA-approved drugs) using structure-based virtual screening approach. A total of 73 hits had a combo score >2.0. Eight different structural scaffold classes were identified, such as one/two tetrahydropyran ring(s), dipeptide/tripeptide/oligopeptide, large (approximately 20 atoms) cyclic peptide, and miscellaneous. The screened hits showed key interactions with sub-pockets of the active site. Further, molecular dynamics studies of selected screened compounds confirmed their perfect fitting into the sub-pockets of the active site. This study suggests promising structures that can fit into the SARS-CoV-2 Mpro active site, and also offers direction for further lead optimization and rational drug design.