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

Abstract

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 μM 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.

Communicated by Ramaswamy H. Sarma

Keywords:

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

Acknowledgment

We thank NYU Shanghai and the ECNU Multifunctional Platform for Innovation (001) for providing us computer time.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (Grant 91753103, 31700646, 21933010), and the Natural Science Foundation of Shanghai (Grant 19ZR1473600).