Ligand-Binding Pocket Shape Differences between Sphingosine 1-Phosphate (S1P) Receptors S1P 1 and S1P 3 Determine Efficiency of Chemical Probe Identification by Ultrahigh-Throughput Screening

Department of Scientific Computing, The Scripps Research Institute, La Jolla, California and Jupiter, Florida, USA.
ACS Chemical Biology (Impact Factor: 5.33). 08/2008; 3(8):486-98. DOI: 10.1021/cb800051m
Source: PubMed


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.

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Available from: Stephan Schurer, Feb 04, 2014
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    • "th an antagonist sphingolipid analog ML - 056 ( W - 146 ) ( Hanson et al . , 2012 ) ( Fig . 6 ) . Unique features of the S1P1 receptor were not predictable from the extensive and rigorous analysis by mutagen - esis previously performed ( Fujiwara et al . , 2007 , 2005 ; Inagaki et al . , 2005 ; Jo et al . , 2005 ; Parrill et al . , 2000a , 2000b ; Schurer et al . , 2008 ; Wang et al . , 2001 ) . The extracellular face of S1P1 receptor is tightly structured ( Hanson et al . , 2012 ) where the N - terminus a - helix folds over the top of the receptor to block access to the binding pocket from the aqueous phase . This static view of the receptor suggests that S1P might require an alternate route into the "
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