An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M
Acrylamide
/ chemistry
Binding Sites
COVID-19
/ pathology
Catalytic Domain
Computational Biology
/ methods
Databases, Protein
Drug Design
Humans
Inhibitory Concentration 50
Molecular Docking Simulation
Protein Kinase Inhibitors
/ chemistry
SARS-CoV-2
/ enzymology
Viral Matrix Proteins
/ antagonists & inhibitors
COVID-19
DOCKovalent
M(pro)
SARS-CoV-2
computer-aided drug discovery
covalent docking
covalent inhibitors
irreversible inhibitors
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
16 12 2021
16 12 2021
Historique:
received:
26
11
2020
revised:
24
03
2021
accepted:
27
05
2021
pubmed:
27
6
2021
medline:
6
1
2022
entrez:
26
6
2021
Statut:
ppublish
Résumé
Designing covalent inhibitors is increasingly important, although it remains challenging. Here, we present covalentizer, a computational pipeline for identifying irreversible inhibitors based on structures of targets with non-covalent binders. Through covalent docking of tailored focused libraries, we identify candidates that can bind covalently to a nearby cysteine while preserving the interactions of the original molecule. We found ∼11,000 cysteines proximal to a ligand across 8,386 complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In a prospective evaluation, five out of nine predicted covalent kinase inhibitors showed half-maximal inhibitory concentration (IC
Identifiants
pubmed: 34174194
pii: S2451-9456(21)00263-4
doi: 10.1016/j.chembiol.2021.05.018
pmc: PMC8228784
pii:
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Viral Matrix Proteins
0
membrane protein, SARS-CoV-2
0
Acrylamide
20R035KLCI
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1795-1806.e5Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests N.L. is a member of the SAB of Totus medicines, Monte Rosa Therapeutics and MetaboMed.
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