20.500.12556/RUL-167856 Nanomolar inhibitor of the galectin-8 N-terminal domain binds via a non-canonical cation-π interaction Galectin-8 is a tandem-repeat galectin consisting of two distinct carbohydrate recognition domains and is a potential drug target. We have developed a library of galectin-8N inhibitors that exhibit high nanomolar Kd values as determined by a competitive fluorescence polarization assay. A detailed thermodynamic analysis of the binding of d-galactosides to galectin-8N by isothermal titration calorimetry reveals important differences in enthalpic and/or entropic contributions to binding. Contrary to expectations, the binding of 2-O-propargyl-d-galactoside was found to strongly increase the binding enthalpy, whereas the binding of 2-O-carboxymethylene-d-galactoside was surprisingly less enthalpy-driven. The results of our work suggest that the ethynyl group can successfully replace the carboxylate group when targeting the water-exposed guanidine moiety of a critical arginine residue. This results in only a minor loss of affinity and an adjusted enthalpic contribution to the overall binding due to non-canonical cation-π interactions, as evidenced by the obtained crystal structure of 2-O-propargyl-d-galactoside in complex with the N-terminal domain of galectin-8. Such an interaction has neither been identified nor discussed to date in a small-molecule ligand-protein complex. carbohydrates lead optimization structure-based drug design X-ray crystallography ogljikovi hidrati optimizacija potencialnih strank oblikovanje zdravil na osnovi strukture rentgenska kristalografija farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2025-03-17 11:19:08 2025-03-17 11:19:16 2025-03-18 03:56:37 0000-00-00 00:00:00 2025 0 0 11 str. article 59 Vol. 8 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 2399-3669 10.1038/s42004-025-01458-6 229077763 s42004-025-01458-6.pdf s42004-025-01458-6.pdf 1 EAB02C81AC085713926C5F84C22150C6 a673a3558b28b9ae89b8c77ea91cb5d99d252a53fb0d27229b2737bd63a8de2f 23ad35c6-031a-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=200725 https://www.nature.com/articles/s42004-025-01458-6 1 484774e6-0318-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=200724 Fakulteta za farmacijo 0 0 0