8DIG

Virtual screening for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Summary for 8DIG

• Entry DOI: 10.2210/pdb8dig/pdb
• Descriptor: 3C-like proteinase nsp5, (3P)-1-[(4-fluorophenyl)methyl]-3-(isoquinolin-4-yl)imidazolidine-2,4-dione (3 entities in total)
• Functional Keywords: sars-cov2, mpro, nsp7, covid-19, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2, COVID-19 virus)
• Total number of polymer chains: 2
• Total formula weight: 67986.43

Authors

Singh, I.,Shoichet, B.K. (deposition date: 2022-06-29, release date: 2023-06-28, Last modification date: 2023-10-25)

Primary citation

Fink, E.A.,Bardine, C.,Gahbauer, S.,Singh, I.,Detomasi, T.C.,White, K.,Gu, S.,Wan, X.,Chen, J.,Ary, B.,Glenn, I.,O'Connell, J.,O'Donnell, H.,Fajtova, P.,Lyu, J.,Vigneron, S.,Young, N.J.,Kondratov, I.S.,Alisoltani, A.,Simons, L.M.,Lorenzo-Redondo, R.,Ozer, E.A.,Hultquist, J.F.,O'Donoghue, A.J.,Moroz, Y.S.,Taunton, J.,Renslo, A.R.,Irwin, J.J.,Garcia-Sastre, A.,Shoichet, B.K.,Craik, C.S.
Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors.
Protein Sci., 32:e4712-e4712, 2023

PubMed Abstract: 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 (M ), 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 IC 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 M inhibitors for SARS-CoV-2, the modest success rate also reveals weaknesses in our approach for challenging targets like M versus other targets where it has been more successful, and versus other structure-based techniques against M itself.

PubMed: 37354015
DOI: 10.1002/pro.4712

Experimental method

X-RAY DIFFRACTION (2.45 Å)