Molecular recognition in the sphingosine 1-phosphate receptor family

Truc Chi T Pham, James I. Fells, Daniel A. Osborne, E. Jeffrey North, Mor M. Naor, Abby L. Parrill

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 S1P1-5 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 S1P4 and S1P5 receptors, and suggests significant structural differences of the S1P2 receptor. Docking results reveal a previously unknown sulfur-aromatic interaction between the S1P4 C5.44 sulfur atom and the phenyl ring of benzimidazole as well as π-π interaction between F3.33 of S1P1,4,5 and aromatic ligands. The findings not only confirm the importance of a cation-π interaction between W4.64 and the ammonium of S1P at S1P4 but also predict the same interaction at S1P5. 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.

Original languageEnglish
Pages (from-to)1189-1201
Number of pages13
JournalJournal of Molecular Graphics and Modelling
Volume26
Issue number8
DOIs
StatePublished - Jun 2008
Externally publishedYes

Fingerprint

Sphingosines
Lysosphingolipid Receptors
Molecular recognition
phosphates
Phosphates
Ligands
ligands
Sulfur
interactions
sulfur
selectivity
Ammonium Compounds
Cations
Screening
homology
Positive ions
Atoms

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Spectroscopy
  • Atomic and Molecular Physics, and Optics

Cite this

Molecular recognition in the sphingosine 1-phosphate receptor family. / Pham, Truc Chi T; Fells, James I.; Osborne, Daniel A.; North, E. Jeffrey; Naor, Mor M.; Parrill, Abby L.

In: Journal of Molecular Graphics and Modelling, Vol. 26, No. 8, 06.2008, p. 1189-1201.

Research output: Contribution to journalArticle

Pham, Truc Chi T ; Fells, James I. ; Osborne, Daniel A. ; North, E. Jeffrey ; Naor, Mor M. ; Parrill, Abby L. / Molecular recognition in the sphingosine 1-phosphate receptor family. In: Journal of Molecular Graphics and Modelling. 2008 ; Vol. 26, No. 8. pp. 1189-1201.
@article{e8b576a9172441548b6389909a7a7b5c,
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 S1P1-5 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 S1P4 and S1P5 receptors, and suggests significant structural differences of the S1P2 receptor. Docking results reveal a previously unknown sulfur-aromatic interaction between the S1P4 C5.44 sulfur atom and the phenyl ring of benzimidazole as well as π-π interaction between F3.33 of S1P1,4,5 and aromatic ligands. The findings not only confirm the importance of a cation-π interaction between W4.64 and the ammonium of S1P at S1P4 but also predict the same interaction at S1P5. 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.",
author = "Pham, {Truc Chi T} and Fells, {James I.} and Osborne, {Daniel A.} and North, {E. Jeffrey} and Naor, {Mor M.} and Parrill, {Abby L.}",
year = "2008",
month = "6",
doi = "10.1016/j.jmgm.2007.11.001",
language = "English",
volume = "26",
pages = "1189--1201",
journal = "Journal of Molecular Graphics and Modelling",
issn = "1093-3263",
publisher = "Elsevier Inc.",
number = "8",

}

TY - JOUR

T1 - Molecular recognition in the sphingosine 1-phosphate receptor family

AU - Pham, Truc Chi T

AU - Fells, James I.

AU - Osborne, Daniel A.

AU - North, E. Jeffrey

AU - Naor, Mor M.

AU - Parrill, Abby L.

PY - 2008/6

Y1 - 2008/6

N2 - 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 S1P1-5 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 S1P4 and S1P5 receptors, and suggests significant structural differences of the S1P2 receptor. Docking results reveal a previously unknown sulfur-aromatic interaction between the S1P4 C5.44 sulfur atom and the phenyl ring of benzimidazole as well as π-π interaction between F3.33 of S1P1,4,5 and aromatic ligands. The findings not only confirm the importance of a cation-π interaction between W4.64 and the ammonium of S1P at S1P4 but also predict the same interaction at S1P5. 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.

AB - 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 S1P1-5 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 S1P4 and S1P5 receptors, and suggests significant structural differences of the S1P2 receptor. Docking results reveal a previously unknown sulfur-aromatic interaction between the S1P4 C5.44 sulfur atom and the phenyl ring of benzimidazole as well as π-π interaction between F3.33 of S1P1,4,5 and aromatic ligands. The findings not only confirm the importance of a cation-π interaction between W4.64 and the ammonium of S1P at S1P4 but also predict the same interaction at S1P5. 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.

UR - http://www.scopus.com/inward/record.url?scp=42749089941&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42749089941&partnerID=8YFLogxK

U2 - 10.1016/j.jmgm.2007.11.001

DO - 10.1016/j.jmgm.2007.11.001

M3 - Article

C2 - 18165127

AN - SCOPUS:42749089941

VL - 26

SP - 1189

EP - 1201

JO - Journal of Molecular Graphics and Modelling

JF - Journal of Molecular Graphics and Modelling

SN - 1093-3263

IS - 8

ER -