Mapping protein binding sites by photoreactive fragment pharmacophores

Fragment screening, a popular strategy for drug discovery, often faces challenges due to weak fragment affinities. This study introduces a screening concept that combines evolutionary optimized fragment pharmacophores with a photoaffinity handle, enabling high hit rates via LC-MS detection. The sensitivity is enhanced by a target-conjugated photocatalyst. 100 diazirine-tagged fragments were screened against six protein targets (three benchmark and three therapeutically relevant). The study discovered several fragment hits, identified their binding sites, and demonstrated the protocol's superior performance compared to traditional methods.

Péter Ábrányi-Balogh, Dávid Bajusz, Zoltán Orgován, Aaron B. Keeley, László Petri, Nikolett Péczka, Tibor Viktor Szalai, Gyula Pálfy, Márton Gadanecz, Emma K. Grant, Tímea 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