Studies on selectin blocker. 3. Investigation of the carbohydrate ligand sialyl Lewis X recognition site of P-selectin.

We have previously found that a 1-deoxy sialyl Lewis X (3), which lacks only the C-1 hydroxyl group of sialyl Lewis X (sLeX), exhibited up to 20 times more potency than the sLeX toward P-selectin binding. In order to explain the structure-activity relationship, we constructed structural models of the complexes of P-selectin and compounds 1-3 and sLeX. From the modeling analysis, we found that the carbonyl oxygen of the N-acetyl group of GlcNAc in 3 formed a hydrogen bond with the amide group of Asn 82 in P-selectin. We also supposed that there was a hydrophobic interaction between the pyranose of GlcNAc in compound 3 and the imidazole ring of His 108 in P-selectin. However, it is considered that those interactions would not be appreciable in the case of sLeX or other 1-deoxy sLeX analogs (1,2). Accordingly, our results could be helpful in obtaining a new concept to design a potent inhibitor toward P-selectin binding.