title: Molecular recognition in the sphingosine 1-phosphate receptor family.
abstract: Computational modeling and its application in ligand screening and ligand receptor interaction studies play important roles in structure-based drug design. A series of sphingosine 1-phosphate (S1P) receptor ligands with varying potencies and receptor selectivities were docked into homology models of the S1P(1-5) receptors. These studies provided molecular insights into pharmacological trends both across the receptor family as well as at single receptors. This study identifies ligand recognition features that generalize across the S1P receptor family, features unique to the S1P(4) and S1P(5) receptors, and suggests significant structural differences of the S1P(2) receptor. Docking results reveal a previously unknown sulfur-aromatic interaction between the S1P(4) C5.44 sulfur atom and the phenyl ring of benzimidazole as well as pi-pi interaction between F3.33 of S1P(1,4,5) and aromatic ligands. The findings not only confirm the importance of a cation-pi interaction between W4.64 and the ammonium of S1P at S1P(4) but also predict the same interaction at S1P(5). S1P receptor models are validated for pharmacophore development including database mining and new ligand discovery and serve as tools for ligand optimization to improve potency and selectivity.
authors.affiliation: Department of Chemistry and Computational Research on Materials Institute, The University of Memphis, Memphis, TN 38152, USA.
authors.forename: Truc-Chi T
authors.initials: TC
authors.lastname: Pham
authors.forename: James I
authors.initials: JI
authors.lastname: Fells
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Osborne
authors.forename: E Jeffrey
authors.initials: EJ
authors.lastname: North
authors.forename: Mor M
authors.initials: MM
authors.lastname: Naor
authors.forename: Abby L
authors.initials: AL
authors.lastname: Parrill
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D049368:Receptors, Lysophosphatidic Acid / Q000737:chemistry*; D049349:Receptors, Lysosphingolipid / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D049368:Receptors, Lysophosphatidic Acid; D049349:Receptors, Lysosphingolipid