Discovery of novel inhibitors of SARS-CoV-2 main protease

作者：Zheng, Lei; Chen, Yanmei; Bao, Jingxiao; He, Liping; Dong, Suzhen^*; Qi, Yifei^*; Zhang, John Z. H.

来源：Journal of Biomolecular Structure and Dynamics, 2022, 40(23): 12526-12534.

DOI：10.1080/07391102.2021.1972041

• COVID-19
• main protease
• inhibitory activity
• virtual screening

Corona Virus Disease 2019 (COVID-19), referred to as `New Coronary Pneumonia', is a type of acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. M-pro is one of the main targets for treating COVID-19. The current research on M-pro mainly focuses on the repurposing of old drugs, and there are only a few novel ligands that inhibit M-pro. In this research, we used computational free energy calculation to screen a compound library against M-pro, and discovered four novel compounds with the two best compounds (AG-690/13507628 and AG-690/13507724) having experimental measured IC50 of just under 3 mu M and low cell toxicity. Detailed decomposition of the interactions between the inhibitors and M-pro reveals key interacting residues and interactions that determine the activity. The results from this study should provide a basis for further development of anti-SARS-CoV-2 drugs.