biostudies-literatureGlaser JUT-BattelleOak Ridge National Laboratory255-265https://www.ebi.ac.uk/biostudies/studies/S-EPMC9003389biostudies-literatureUnknown5(4)Inhibition of the SARS-CoV-2 main protease (M^pro) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of M^pro. Starting from a recently discovered scaffold (The COVID Moonshot Consortium. Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics. bioRxiv 2020.10.29.339317) represented by an isoquinoline series, we searched a database of over a billion compounds using a cheminformatics molecular fingerprinting approach. We identified and tested 48 compounds in enzyme inhibition assays, of which 21 exhibited inhibitory activity above 50% at 20 μM. Among these, four compounds with IC₅₀ values around 1 μM were found. Interestingly, despite the large search spaceACS pharmacology & translational scienceHit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor.PMC9003389DE-AC05-00OR22725LOIS 10126Kovalevsky AParks JMSmith DMALabbe ACoates LDel Galdo SAgarwal RSedova ADavidson RBMaradzike EGlaser JBykov DDaidone IKneller DWHsu DJGalanie STharrington ASmith JCfalseHit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor.Inhibition of the SARS-CoV-2 main protease (M^pro) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of M^pro. Starting from a recently discovered scaffold (The COVID Moonshot Consortium. Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics. bioRxiv 2020.10.29.339317) represented by an isoquinoline series, we searched a database of over a billion compounds using a cheminformatics molecular fingerprinting approach. We identified and tested 48 compounds in enzyme inhibition assays, of which 21 exhibited inhibitory activity above 50% at 20 μM. Among these, four compounds with IC₅₀ values around 1 μM were found. Interestingly, despite the large search space2022-01-01T00:00:00Z2022 Apr2026-05-09T17:37:21.613Z2024-11-10T08:43:41.215ZS-EPMC90033893543453110.1021/acsptsci.2c00026