Ensemble docking based virtual screening of SARS-CoV-2 main protease inhibitors.
Mol Inform
; 43(8): e202300279, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-38973780
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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Base de dados:
MEDLINE
Assunto principal:
Antivirais
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Inibidores de Proteases
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Simulação de Acoplamento Molecular
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Proteases 3C de Coronavírus
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SARS-CoV-2
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article