Proposition of a new allosteric binding site for potential SARS-CoV-2 3CL protease inhibitors by utilizing molecular dynamics simulations and ensemble docking

Abstract

The SARS-CoV-2 3CL protease shows a high similarity with 3CL proteases of other beta-coronaviruses, such as SARS and MERS. It is the main enzyme involved in generating various non-structural proteins that are important for viral replication and is one of the most important proteins responsible for SARS-CoV-2 virulence. In this study, we have conducted ensemble docking of molecules from the DrugBank database using both crystallographic structure of the SARS-CoV-2 3CLpro, as well as five conformations obtained after performing a cluster analysis of a 300 ns molecular dynamics simulation. This procedure elucidated the inappropriateness of the active site for non-covalent inhibitors, but it has also shown that there exists an additional, more favorable, allosteric binding site, which could be a better target for non-covalent inhibitors, as it could prevent dimerization and activation of SARS-CoV-2 3CLpro.

Design of peptide-based coronavirus inhibitors that target disruption of 3CLpro protease self-association

“…3a and c). Ligand binding to the groove between domains II and III has been proposed to allosterically undermine 3CLpro dimerization 27,68,69 into the active dimeric form. This suggests that peptide binding to this region of the 3CLpro monomer has the potential to disrupt dimer formation.…”