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

J Med Chem. 1996 Nov 8;39(23):4547-53. doi: 10.1021/jm960134g.

Abstract

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.

MeSH terms

  • Amino Acid Sequence
  • Humans
  • Hydrogen Bonding
  • Lectins / metabolism
  • Ligands
  • Molecular Sequence Data
  • Oligosaccharides / metabolism*
  • P-Selectin / drug effects
  • P-Selectin / metabolism*
  • Protein Binding
  • Protein Conformation
  • Sialyl Lewis X Antigen
  • Structure-Activity Relationship

Substances

  • Lectins
  • Ligands
  • Oligosaccharides
  • P-Selectin
  • Sialyl Lewis X Antigen