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 galectin-8 N-terminal domain (galectin-8N) with a previously reported quinoline–galactoside ligand at resolution 1.6 Å. Based on this structure, collection galactosides derivatised O3 triazole, benzimidazole, benzothiazole, and benzoxazole moieties were designed synthesised. This led to discovery 3-O-(N-methylbenzimidazolylmethyl)–galactoside Kd 1.8 μM for galectin-8N, most potent selective synthetic galectin-8N date. Molecular dynamics simulations showed that benzimidazole–galactoside derivatives bind non-conserved amino acid Gln47, accounting higher selectivity galectin-8N. Galectin-8 is carbohydrate-binding protein plays key role in pathological lymphangiogenesis, modulation immune system, autophagy. Thus, benzimidazole-derivatised represent promising compounds studies implications galectin-8, as well starting point development anti-tumour anti-inflammatory therapeutics targeting galectin-8.