Design of Non-Carbohydrate Selectin Blockers by Molecular Modeling

• Published in: Journal of the Mass Spectrometry Society of Japan 1999, Vol.47(3), pp.129-134
• Main Authors: TSUJISHITA, Hideki, HIRAMATSU, Yasuyuki, KONDO, Hirosato
• Format: Article
• Language: English
• Subjects: Binding; Blocking; Carbohydrates; Design engineering; Dipeptides; Functional groups; GSC-150; Mathematical models; Molecular dynamics; Orientation; Scaffolds; Type II β-turn
• ISSN: 1340-8097; 1880-4225
• DOI: 10.5702/massspec.47.129

A design of non-carbohydrate selectin blockers based on a carbohydrate compound is described. We first investigated the mode of interaction between selectin and its carbohydrate ligand, GSC-150. GSC-150 has a sulfated sugar unit and a branched long alkyl chain (B-30). From a molecular dynamics simulation of the complex of GSC-150 with E-selectin in water, we found the essential three functional groups of GSC-150 necessary for binding toward selectin: namely, the negatively-charged sulfate, the fucose, and B-30. Especially, B-30 would play an important role in the tight hydrophobic interaction with selectin. The lactose unit of GSC-150 may serve as a scaffold that keeps those functional groups to their proper orientation. Next we searched for another scaffold, and found that the modified Ser-Glu dipeptides could be good surrogates. They are about 50 to 100-fold more potent blocker than GSC-150. A detailed analysis of their binding mode suggested that the dipeptide backbone could adopt type-II β-turn conformation, a minor subtype of β-turn, in their bound state. This type-II β-turn would be necessary to fix the critical functional groups in the dipeptides to their proper orientation.