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Molecules 2017, 22(3), 449; doi:10.3390/molecules22030449

Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding

Molecular Recognition Section (MRS), Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MA 20892, USA
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Academic Editor: Francisco Ciruela
Received: 5 February 2017 / Revised: 2 March 2017 / Accepted: 6 March 2017 / Published: 11 March 2017
(This article belongs to the Special Issue Adenosine Receptors)
View Full-Text   |   Download PDF [2382 KB, uploaded 11 March 2017]   |  

Abstract

Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A1, A2A, A2B and A3, which belong to the G protein-coupled receptor (GPCR) superfamily. The human A3AR (hA3AR) subtype is implicated in several cytoprotective functions. Therefore, hA3AR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anticancer, and cardioprotective agents. Structure-based molecular modeling techniques have been applied over the years to rationalize the structure–activity relationships (SARs) of newly emerged A3AR ligands, guide the subsequent lead optimization, and interpret site-directed mutagenesis (SDM) data from a molecular perspective. In this review, we showcase selected modeling-based and guided strategies that were applied to elucidate the binding of agonists to the A3AR and discuss the challenges associated with an accurate prediction of the receptor extracellular vestibule through homology modeling from the available X-ray templates. View Full-Text
Keywords: G protein-coupled receptor; site-directed mutagenesis; homology modeling; adenosine receptor; structure-activity relationship; nucleoside; docking; molecular dynamics; agonist; drug discovery; virtual screening G protein-coupled receptor; site-directed mutagenesis; homology modeling; adenosine receptor; structure-activity relationship; nucleoside; docking; molecular dynamics; agonist; drug discovery; virtual screening
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Ciancetta, A.; Jacobson, K.A. Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding. Molecules 2017, 22, 449.

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