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

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^Pro ), 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

SUBMITTER: Fink EA 

PROVIDER: S-EPMC10364469 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature