Studies on Selectin Blocker. 3. Investigation of the Carbohydrate Ligand Sialyl Lewis X Recognition Site of P-Selectin

• Published in: Journal of medicinal chemistry 1996-11, Vol.39 (23), p.4547-4553
• Main Authors: Hiramatsu, Yasuyuki, Tsujishita, Hideki, Kondo, Hirosato
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Humans; Hydrogen Bonding; Lectins - metabolism; Ligands; Medical sciences; Molecular Sequence Data; Oligosaccharides - metabolism; P-Selectin - drug effects; P-Selectin - metabolism; Pharmacology. Drug treatments; Protein Binding; Protein Conformation; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960134g

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.