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Molecular Docking Screening Using Agonist-Bound GPCR Structures: Probing the A(2A) Adenosine Receptor
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center (SeRC), Sweden.
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2015 (English)In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 55, no 3, 550-563 p.Article in journal (Refereed) Published
Abstract [en]

Crystal structures of G protein-coupled receptors (GPCRs) have recently revealed the molecular basis of ligand binding and activation, which has provided exciting opportunities for structure-based drug design. The A(2A) adenosine receptor (A(2A)AR) is a promising therapeutic target for cardiovascular diseases, but progress in this area is limited by the lack of novel agonist scaffolds. We carried out docking screens of 6.7 million commercially available molecules against active-like conformations of the A(2A)AR to investigate whether these structures could guide the discovery of agonists. Nine out of the 20 predicted agonists were confirmed to be A(2A)AR ligands, but none of these activated the ARs. The difficulties in discovering AR agonists using structure-based methods originated from limited atomic-level understanding of the activation mechanism and a chemical bias toward antagonists in the screened library. In particular, the composition of the screened library was found to strongly reduce the likelihood of identifying AR agonists, which reflected the high ligand complexity required for receptor activation. Extension of this analysis to other pharmaceutically relevant GPCRs suggested that library screening may not be suitable for targets requiring a complex receptor-ligand interaction network. Our results provide specific directions for the future development of novel A(2A)AR agonists and general strategies for structure-based drug discovery.

Place, publisher, year, edition, pages
2015. Vol. 55, no 3, 550-563 p.
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Chemical Sciences Basic Medicine Computer and Information Science
URN: urn:nbn:se:su:diva-117016DOI: 10.1021/ci500639gISI: 000351652900008PubMedID: 25625646OAI: diva2:810094


Available from: 2015-05-06 Created: 2015-05-05 Last updated: 2015-05-06Bibliographically approved

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Rodriguez, DavidCarlsson, Jens
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Department of Biochemistry and BiophysicsScience for Life Laboratory (SciLifeLab)
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ReferencesLink to record
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