Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Elissa A. Fink, Conner Bardine, Stefan Gahbauer, Isha Singh, Tyler C. Detomasi, Kris White, Shuo Gu, Xiaobo Wan, Jun Chen, Beatrice Ary, Isabella Glenn, Joseph O'Connell, Henry O'Donnell, Pavla Fajtová, Jiankun Lyu, Seth Vigneron, Nicholas J. Young, Ivan S. Kondratov, Arghavan Alisoltani, Lacy M. SimonsRamon Lorenzo-Redondo, Egon A. Ozer, Judd F. Hultquist, Anthony J. O'Donoghue, Yurii S. Moroz, Jack Taunton, Adam R. Renslo, John J. Irwin, Adolfo García-Sastre, Brian K. Shoichet, Charles S. Craik

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Antiviral therapeutics to treat SARS-CoV-2 are needed to diminish the morbidity of the ongoing COVID-19 pandemic. A well-precedented drug target is the main viral protease (MPro), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure-based approach, we docked 1.2 billion non-covalent lead-like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 and 20 μM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of MPro inhibitors for SARS-CoV-2, the modest success rate also reveals weaknesses in our approach for challenging targets like MPro versus other targets where it has been more successful, and versus other structure-based techniques against MPro itself.

Original languageEnglish
Article numbere4712
JournalProtein Science
Issue number8
StatePublished - Aug 2023


  • SARS-COV-2
  • discoverydockinganti-viral
  • major protease
  • structure-based inhibitor


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