Journal
NEUROPHARMACOLOGY
Volume 60, Issue 1, Pages 108-115Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2010.07.009
Keywords
GPCR; G protein-coupled receptor; Adenosine receptor; Subtype selectivity; Homology modeling; Ligand docking; Conformational sampling; Structure based drug discovery
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Funding
- National Institutes of Health [R01-GM071872, 1R43MH084374-01A1]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM074832, R01GM071872] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R43MH084374] Funding Source: NIH RePORTER
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One of the major hurdles in the development of safe and effective drugs targeting G-protein coupled receptors (GPCRs) is finding ligands that are highly selective for a specific receptor subtype. Structural understanding of subtype-specific binding pocket variations and ligand receptor interactions may greatly facilitate design of selective ligands. To gain insights into the structural basis of ligand subtype selectivity within the family of adenosine receptors (AR: A(1), A(2A), A(2B), and A(3)) we generated 3D models of all four subtypes using the recently determined crystal structure of the A(A2)AR as a template, and employing the methodology of ligand-guided receptor optimization for refinement. This approach produced 3D conformational models of AR subtypes that effectively explain binding modes and subtype selectivity for a diverse set of known AR antagonists. Analysis of the subtype-specific ligand receptor interactions allowed identification of the major determinants of ligand selectivity, which may facilitate discovery of more efficient drug candidates. (C) 2010 Elsevier Ltd. All rights reserved.
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