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Mapping protein binding sites by photoreactive fragment pharmacophores

2024; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/s42004-024-01252-w

2399-3669

Péter Ábrányi‐Balogh, Dávid Bajusz, Zoltán Orgován, Aaron Keeley, László Petri, Nikolett Péczka, Tibor V. Szalai, Gyula Pálfy, Márton Gadanecz, Emma K. Grant, Tı́mea Imre, Tamás Takács, Ivan Ranđelović, Marcell Baranyi, András Marton, Gitta Schlosser, Qirat F. Ashraf, Elvin D. de Araujo, Tamás Karancsi, László Buday, József Tóvári, András Perczel, Jacob T. Bush, György M. Keserű,

Chemical Synthesis and Analysis

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