Fragment-based development of triazole-substituted O-galactosyl aldoximes with fragment-induced affinity and selectivity for galectin-3.
A fragment-based development of 3C-triazol-1-yl-O-galactopyranosyl aldoximes led to the discovery of highly selective and high affinity (K(d) down to 11 microm) small monosaccharide based inhibitors of galectin-3. Galectin-7, 8 N-terminal CRD, and 9 N-terminal CRD bound the inhibitors only weakly. The galectin-3 selectivity was hypothesized to stem from interaction of the aldoxime moiety with a site not present in the other galectins.
Tejler
Johan
J
Organic Chemistry, Lund University, POB 124, SE-22100, Lund, Sweden.
Salameh
Bader
B
Leffler
Hakon
H
Nilsson
Ulf J
UJ
D000215:Acylation; D001665:Binding Sites; D055808:Drug Discovery; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006898:Hydroxylamines / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D014230:Triazoles / Q000737:chemistry*
D037502:Galectin 3; D006898:Hydroxylamines; D010091:Oximes; D014230:Triazoles