20.500.12556/RUL-141507 Benzimidazole-galactosides bind selectively to the galectin-8 N-terminal domain structure-based design and optimisation We have obtained the X-ray crystal structure of the galectin-8 N-terminal domain (galectin-8N) with a previously reported quinoline-galactoside ligand at a resolution of 1.6Å. Based on this X-ray structure, a collection of galactosides derivatised at O3 with triazole, benzimidazole, benzothiazole, and benzoxazole moieties were designed and synthesised. This led to the discovery of a 3-O-(N-methylbenzimidazolylmethyl)-galactoside with a Kd of 1.8%[micro]M for galectin-8N, the most potent selective synthetic galectin-8N ligand to date. Molecular dynamics simulations showed that benzimidazole-galactoside derivatives bind the non-conserved amino acid Gln47, accounting for the higher selectivity for galectin-8N. Galectin-8 is a carbohydrate-binding protein that plays a key role in pathological lymphangiogenesis, modulation of the immune system, and autophagy. Thus, the benzimidazole-derivatised galactosides represent promising compounds for studies of the pathological implications of galectin-8, as well as a starting point for the development of anti-tumour and anti-inflammatory therapeutics targeting galectin-8. benzimidazole galectin-8N quinoline selectivity molecular dynamics x-ray crystallography true false true Angleški jezik Angleški jezik Članek v reviji 2022-09-30 09:12:51 2022-09-30 09:12:53 2022-10-01 04:09:41 0000-00-00 00:00:00 2021 0 0 Str. 1-13 Vol. 223 art. 113664 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 0223-5234 10.1016/j.ejmech.2021.113664 68254211 1-s2.0-S0223523421005134-main.pdf 1-s2.0-S0223523421005134-main.pdf 1 E72C4AE8A62AFE2051CB0080314F66E8 c9537d50ab0939e2fb097868f2528e181ebd4203412f91ece9f2e20b6d14555c 8d759cd3-408f-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=162586 https://www.sciencedirect.com/science/article/pii/S0223523421005134?via%3Dihub 1 4a10e317-408f-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=162584 Fakulteta za farmacijo 0 0 0