Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening.
Journal
Journal of the American Chemical Society
ISSN: 1520-5126
Titre abrégé: J Am Chem Soc
Pays: United States
ID NLM: 7503056
Informations de publication
Date de publication:
05 06 2019
05 06 2019
Historique:
pubmed:
8
5
2019
medline:
12
9
2020
entrez:
8
5
2019
Statut:
ppublish
Résumé
Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, but such electrophilic fragments were considered nonselective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against 10 cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. In contrast, we found hits for most targets. Combining our approach with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2 and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlights the potential of electrophile-fragment screening as a practical and efficient tool for covalent-ligand discovery.
Identifiants
pubmed: 31060360
doi: 10.1021/jacs.9b02822
pmc: PMC6556873
doi:
Substances chimiques
Ligands
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8951-8968Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N002679/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106169/Z/14/Z
Pays : United Kingdom
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