| Fragment Screening of GPCRs Using Biophysical Methods: Identification of Ligands of the Adenosine A2A Receptor with Novel Biological Activity. | |
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MedLine Citation:
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PMID: 23013674 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Dan Chen; James C Errey; Laura H Heitman; Fiona H Marshall; Adriaan P Ijzerman; Gregg David Siegal |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-9-26 |
Journal Detail:
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Title: ACS chemical biology Volume: - ISSN: 1554-8937 ISO Abbreviation: ACS Chem. Biol. Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-9-27 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101282906 Medline TA: ACS Chem Biol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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