Ligand-Binding Pocket Shape Differences between Sphingosine 1-Phosphate (S1P) Receptors S1P1 and S1P3 Determine Efficiency of Chemical Probe Identification by Ultrahigh-Throughput Screening
| Autor: | Timothy P. Spicer, Peter Hodder, Pedro J. Gonzalez-Cabrera, Steven J. Brown, Peter Chase, Jacqueline Chapman, Hugh Rosen, Marie Therese Schaeffer, Euijung Jo, Stephan C. Schürer |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Agonist Protein Conformation medicine.drug_class Sphingosine-1-phosphate receptor Biosensing Techniques CHO Cells Biology Ligands Biochemistry Article Structure-Activity Relationship chemistry.chemical_compound Cricetulus Cricetinae medicine Animals Cluster Analysis Sphingosine-1-phosphate Phosphorylation Binding site Receptor Oxadiazoles Binding Sites General Medicine Ligand (biochemistry) Receptors Lysosphingolipid chemistry Docking (molecular) Molecular Probes Biophysics Molecular Medicine Calcium 5-HT1 receptor Protein Binding |
| Zdroj: | ACS Chemical Biology. 3:486-498 |
| ISSN: | 1554-8937 1554-8929 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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