Mapping protein binding sites by photoreactive fragment pharmacophores.

ABSTRACT: 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

SUBMITTER: Abranyi-Balogh P 

PROVIDER: S-EPMC11292009 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature