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

Research output: Contribution to journalArticlepeer-review


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. Mpro is one of the main targets for treating COVID-19. The current research on Mpro mainly focuses on the repurposing of old drugs, and there are only a few novel ligands that inhibit Mpro. In this research, we used computational free energy calculation to screen a compound library against Mpro, 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 Mpro 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.

Original languageEnglish (US)
Pages (from-to)12526-12534
Number of pages9
JournalJournal of Biomolecular Structure and Dynamics
Issue number23
StatePublished - 2022


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

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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