AI Article Synopsis
- X-ray structures of coronavirus drug targets were rapidly acquired during the early COVID-19 pandemic, especially focusing on the main protease (Mpro) of SARS-CoV-2, which is crucial for developing direct antiviral drugs.
- A systematic, semi-automated method was developed to select the best ensemble of Mpro structures for virtual screening of potential inhibitors, as the selection process was complex.
- This method was validated against existing approaches and led to the discovery of new thienopyrimidinone derivatives that effectively inhibit the Mpro enzyme.
Article Abstract
During the first years of COVID-19 pandemic, X-ray structures of the coronavirus drug targets were acquired at an unprecedented rate, giving hundreds of PDB depositions in less than a year. The main protease (Mpro) of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is the primary validated target of direct-acting antivirals. The selection of the optimal ensemble of structures of Mpro for the docking-driven virtual screening campaign was thus non-trivial and required a systematic and automated approach. Here we report a semi-automated active site RMSD based procedure of ensemble selection from the SARS-CoV-2 Mpro crystallographic data and virtual screening of its inhibitors. The procedure was compared with other approaches to ensemble selection and validated with the help of hand-picked and peer-reviewed activity-annotated libraries. Prospective virtual screening of non-covalent Mpro inhibitors resulted in a new chemotype of thienopyrimidinone derivatives with experimentally confirmed enzyme inhibition.
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| http://dx.doi.org/10.1002/minf.202300279 | DOI Listing |
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