| Design of Non-Carbohydrate Selectin Blockers by Molecular Modeling |
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*a) Nippon-Organon Research & Development Laboratories (1-5-90 Tomobuchi-cho, Miyakojima-ku, Osaka 534-8666, Japan) † Present address: Bayer Yakuhin Research Center Kyoto (6-5-1-3 Kunimidai, Kizu-cho, Soraku-gun, Kyoto 619-0216, Japan) |
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| 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. | ||
| Key words: GSC-150, Molecular dynamics, Dipeptides, Type II β-turn | ||
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