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

Lei Zheng; Yanmei Chen; Jingxiao Bao; Liping He; Suzhen Dong; Yifei Qi; John Z H Zhang

doi:10.1080/07391102.2021.1972041

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

J Biomol Struct Dyn. 2022;40(23):12526-12534. doi: 10.1080/07391102.2021.1972041. Epub 2021 Sep 2.

Authors

Lei Zheng¹, Yanmei Chen¹, Jingxiao Bao¹, Liping He¹, Suzhen Dong¹, Yifei Qi^{1

2}, John Z H Zhang^{1

2

3

4}

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
² NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai, China.
³ Department of Chemistry, New York University, New York, NY, USA.
⁴ Collaborative Innovation Center of Extreme Optics, Shanxi University, Taiyuan, Shanxi, China.

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; inhibitory activity; main protease; virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
COVID-19
Coronavirus 3C Proteases* / antagonists & inhibitors
Drug Discovery / methods
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Protease Inhibitors* / chemistry
Protease Inhibitors* / pharmacology
SARS-CoV-2* / drug effects

Substances

3C-like proteinase, SARS-CoV-2
AG-690
Antiviral Agents
Protease Inhibitors
Coronavirus 3C Proteases

Grants and 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).