20.500.12556/RUL-185272 Mapping functionally relevant tractable lysines of challenging protein targets by covalent fragment screening Covalent fragment screening has become an established strategy for identifying targetable amino acid residues or viable chemical starting points against challenging protein targets. In recent years, lysine has received growing interest as a nucleophilic residue suitable for covalent labelling. Herein, we present a lysine-targeting covalent fragment library covering a wide range of warheads. The reactivity and stability of the library members have been systematically characterised, and the library has been subsequently screened against a set of therapeutically relevant and challenging protein targets. We have discovered suitable warheads against the targets and characterised binding sites via enzymatic digestion and modelling. These findings highlight the potential of lysine-targeting covalent chemistry to expand binding site discovery and to support warhead optimisation for diverse protein targets in both medicinal chemistry and chemical biology applications. allosteric sites covalent fragment electrophilic warhead lysine labelling protein–protein interaction alosterična mesta kovalentni fragment elektrofilna bojna glava označevanje lizina interakcija protein-protein farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2026-07-30 10:42:58 2026-07-30 10:43:02 2026-07-31 04:12:03 0000-00-00 00:00:00 2026 0 0 11 str. iss. 11, art. e70421 Vol. 27 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 1439-7633 10.1002/cbic.70421 282801923 ChemBioChem_-_2026_-_Csorba_-_Mapping_Functionally_Relevant_Tractable_Lysines_of_Challenging_Protein_Targets_by_Covalent.pdf ChemBioChem_-_2026_-_Csorba_-_Mapping_Functionally_Relevant_Tractable_Lysines_of_Challenging_Protein_Targets_by_Covalent.pdf 1 772FD5B97764A82AA5741C2A3417EA98 a2f544b2c394f89a1ff37ec835f2e40644697bb7e8d37188939108846b73d8cd a3e2546e-8bf2-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=243630 https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.70421 1 6679806b-8bf2-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=243628 Fakulteta za farmacijo 0 0 0