Noncovalent SARS-COV-2 main protease inhibitors: A virtual screening and molecular dynamic simulation study

Abstract

The main severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease (Mpro, also known as 3CLpro) plays a central role in virus replication, thereby constituting an appealing therapeutic target for coronavirus disease 2019 (COVID-19) treatment. In this study, we used recently reported crystal structures of SARS-CoV-2 Mpro complexed with small-molecule inhibitors. Using the established structure–activity relationships of small-molecule inhibitors of the Mpro of SARS-CoV-2, we used the Virtual Screening Workflow (with hydrogen bond constraints) implemented in Schrödinger Suite 2021 to screen approximately one million compounds in the ChemDiv compound library to identify potential novel noncovalent Mpro inhibitors. Our docking analysis yielded 65 promising lead compounds, the inhibitory activity of which against Mpro was assessed using a fluorescent SARS-CoV-2 Mpro inhibition assay. Notably, six compounds exhibited SARS-CoV-2 Mpro inhibition with IC50 values ranging 22.95–64.63 μM. These hit compounds exhibited good structural diversity, which prompted us to investigate their SARS-CoV-2 Mpro binding modes. We used a previously validated IFD-BPMD-MD workflow to predict the binding positions of these hit compounds. Our simulations showed that these hit complexes exhibited diverse and robust binding to the SARS-CoV-2 Mpro. Our study findings offer valuable insights into the development of novel noncovalent small-molecule protease inhibitor.