Polarizable MD and QM/MM Investigation of Acrylamide-based Leads to Target the Main Protease of SARS-CoV-2

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme for the replication of the virus causing the COVID-19 pandemic. Because there is no known homologue in humans, it has been proposed as a primary target for antiviral drug development. Here, we explore the potential of five acrylamide warhead molecules as possible leads to target MPro by polarizable MD and QM/MM calculations. All calculations involving a classical potential were calculated with the AMOEBA polarizable force field, while electronic structure calculations were performed within the framework of density functional theory. Our MD simulations show that at least one of the analyzed compounds may show promise as a lead for further development as a non-covalent inhibitor. The QM/MM calculations suggest that the compound could be considered as a non-covalent inhibitor, since the formation of a covalent bond with Cys145 has an unfavorable kinetic barrier for that compound.