Mapping protein binding sites by photoreactive fragment pharmacophores.
Journal
Communications chemistry
ISSN: 2399-3669
Titre abrégé: Commun Chem
Pays: England
ID NLM: 101725670
Informations de publication
Date de publication:
31 Jul 2024
31 Jul 2024
Historique:
received:
01
06
2024
accepted:
23
07
2024
medline:
1
8
2024
pubmed:
1
8
2024
entrez:
31
7
2024
Statut:
epublish
Résumé
Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection. The sensitivity of our screening protocol was further improved by a target-conjugated photocatalyst. We have designed, synthesized, and screened 100 diazirine-tagged fragments against three benchmark and three therapeutically relevant protein targets of different tractability. Our therapeutic targets included a conventional enzyme, the first bromodomain of BRD4, a protein-protein interaction represented by the oncogenic KRas
Identifiants
pubmed: 39085342
doi: 10.1038/s42004-024-01252-w
pii: 10.1038/s42004-024-01252-w
doi:
Types de publication
Journal Article
Langues
eng
Pagination
168Informations de copyright
© 2024. The Author(s).
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