title: Structural Probing and Molecular Modeling of the A₃ Adenosine Receptor: A Focus on Agonist Binding.
abstract: Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A₁, A2A, A2Band 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.
authors.affiliation: 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. antonella.ciancetta@nih.gov.
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciancetta
authors.affiliation: 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. kajacobs@helix.nih.gov.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D043684:Receptor, Adenosine A3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D008024:Ligands; D043684:Receptor, Adenosine A3; D000241:Adenosine
keywords: G protein-coupled receptor; adenosine receptor; agonist; docking; drug discovery; homology modeling; molecular dynamics; nucleoside; site-directed mutagenesis; structure-activity relationship; virtual screening