The main protease of SARS-CoV-2 virus, M, is an essential element for viral replication, and inhibitors targeting M are currently being investigated in many drug development programs as a possible treatment for COVID-19. An pilot screen of a highly focused collection of compounds was initiated to identify new lead scaffolds for M. These efforts identified a number of hits. The most effective of these was compound SIMR-2418 having an inhibitory IC value of 20.7 μM. Molecular modeling studies were performed to understand the binding characteristics of the identified compounds. The presence of a cyclohexenone warhead group facilitated covalent binding with the Cys residue of M. Our results highlight the challenges of targeting M protease and pave the way toward the discovery of potent lead molecules.
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