Hydrogen bonding penalty used for virtual screening to discover potent inhibitors for Papain-Like cysteine proteases of SARS-CoV-2.
Chem Biol Drug Des
; 100(4): 502-514, 2022 10.
Article
in English
| MEDLINE | ID: covidwho-1971106
ABSTRACT
The Papain-Like proteases (PLpro) of SARS-CoV-2 play a crucial role in viral replication and the formation of nonstructural proteins. To find available inhibitors, the 3D structure of PLpro of SARS2 was obtained by homologous modelling, and we used this structure as a target to search for inhibitors through molecular docking and MM/GBSA binding free energy rescoring. A novel hydrogen bonding penalty was applied to the screening process, which meanwhile took desolvation into account. Finally, 61 compounds were acquired and 4 of them with IC50 at micromolar level tested in vitro enzyme activity assay, which includes clinical drugs tegaserod. Considering the importance of crystal water molecules, the 4 compounds were re-docked and considered bound waters in the active site as a part of PLpro. The binding modes of these 4 compounds were further explored with metadynamics simulations. The hits will provide a starting point for future key interactions identified and lead optimization targetting PLpro.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Coronavirus Papain-Like Proteases
/
SARS-CoV-2
Type of study:
Prognostic study
Language:
English
Journal:
Chem Biol Drug Des
Journal subject:
Biochemistry
/
Pharmacy
/
Pharmacology
Year:
2022
Document Type:
Article
Affiliation country:
Cbdd.14115
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