Document Detail

Fragment Screening of GPCRs Using Biophysical Methods: Identification of Ligands of the Adenosine A2A Receptor with Novel Biological Activity.
MedLine Citation:
PMID:  23013674     Owner:  NLM     Status:  Publisher    
Fragment-based drug discovery (FBDD) has proven a powerful method to develop novel drugs with excellent oral bioavailability against challenging pharmaceutical targets such as protein-protein interaction targets. Very recently the underlying biophysical techniques have begun to be successfully applied to membrane proteins. Here we show that novel, ligand efficient small molecules with a variety of biological activities can be found by screening a small fragment library using ther-mostabilized (StaR) G protein-coupled receptors (GPCRs) and Target Immobilized NMR Screening (TINS). Detergent solubilized, StaR adenosine A2A receptor was immobilized with retention of functionality and a screen of 531 fragments was performed. Hits from the screen were thoroughly characterized for biochemical activity using the wild-type receptor. Both orthosteric and allosteric modulatory activity has been demonstrated in biochemi-cal validation assays. Allosteric activity was confirmed in cell-based functional assays. The validated fragment hits make excellent starting points for a subsequent hit-to-lead elaboration program.
Dan Chen; James C Errey; Laura H Heitman; Fiona H Marshall; Adriaan P Ijzerman; Gregg David Siegal
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-26
Journal Detail:
Title:  ACS chemical biology     Volume:  -     ISSN:  1554-8937     ISO Abbreviation:  ACS Chem. Biol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101282906     Medline TA:  ACS Chem Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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