title: Ligand-binding pocket shape differences between sphingosine 1-phosphate (S1P) receptors S1P1 and S1P3 determine efficiency of chemical probe identification by ultrahigh-throughput screening.
abstract: We have studied the sphingosine 1-phosphate (S1P) receptor system to better understand why certain molecular targets within a closely related family are much more tractable when identifying compelling chemical leads. Five medically important G-protein-coupled receptors for S1P regulate heart rate, coronary artery caliber, endothelial barrier integrity, and lymphocyte trafficking. Selective S1P receptor agonist probes would be of great utility to study receptor subtype-specific function. Through systematic screening of the same libraries, we identified novel selective agonist chemotypes for each of the S1P1 and S1P3 receptors. Ultrahigh-throughput screening (uHTS) for S1P1 was more effective than that for S1P3, with many selective, low nanomolar hits of proven mechanism emerging. Receptor structure modeling and ligand docking reveal differences between the receptor binding pockets, which are the basis for subtype selectivity. Novel selective agonists interact primarily in the hydrophobic pocket of the receptor in the absence of headgroup interactions. Chemistry-space and shape-based analysis of the screening libraries in combination with the binding models explain the observed differential hit rates and enhanced efficiency for lead discovery for S1P1 versus S1P3 in this closely related receptor family.
authors.affiliation: Department of Scientific Computing, The Scripps Research Institute, La Jolla, California and Jupiter, Florida, USA.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schürer
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Brown
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Gonzalez-Cabrera
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Schaeffer
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Chapman
authors.forename: Euijung
authors.initials: E
authors.lastname: Jo
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.forename: Tim
authors.initials: T
authors.lastname: Spicer
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
mesh_terms: D000818:Animals; D001665:Binding Sites; D015374:Biosensing Techniques / Q000379:methods*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D016000:Cluster Analysis; D006224:Cricetinae; D003412:Cricetulus; D008024:Ligands; D008958:Models, Molecular; D015335:Molecular Probes / Q000737:chemistry* / Q000494:pharmacology; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D015335:Molecular Probes; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; D002118:Calcium