Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment

The main protease of SARS-CoV-2 virus, M^pro, is an essential element for viral replication, and inhibitors targeting M^pro are currently being investigated in many drug development programs as a possible treatment for COVID-19. An in vitro pilot screen of a highly focused collection of compounds was initiated to identify new lead scaffolds for M^pro. These efforts identified a number of hits. The most effective of these was compound SIMR-2418 having an inhibitory IC₅₀ 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 Cys¹⁴⁵ residue of M^pro. Our results highlight the challenges of targeting M^pro protease and pave the way toward the discovery of potent lead molecules.