Journal Article

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

Jacobson, Kenneth, Ciancetta, Antonella

2017

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Adenosine / Adenosine - analogs & derivatives / Adenosine - chemical synthesis / Adenosine - pharmacology / Adenosine A3 Receptor Agonists - chemical synthesis / Adenosine A3 Receptor Agonists - pharmacology / Adenosine A3 Receptor Antagonists - chemical synthesis / Adenosine A3 Receptor Antagonists - pharmacology / adenosine receptor / agonist / Anti-Inflammatory Agents - chemical synthesis / Anti-Inflammatory Agents - pharmacology / Antineoplastic Agents - chemical synthesis / Antineoplastic Agents - pharmacology / Cancer / Cardiotonic Agents - chemical synthesis / Cardiotonic Agents - pharmacology / docking / Drug Design / drug discovery / G protein-coupled receptor / homology modeling / Humans / Ligands / Molecular Docking Simulation / molecular dynamics / Molecular Dynamics Simulation / Mutagenesis / Mutagenesis, Site-Directed / nucleoside / Optimization / Phosphorylation / Protein Binding / Protein Conformation / Proteins / Receptor, Adenosine A3 - chemistry / Receptor, Adenosine A3 - genetics / Receptor, Adenosine A3 - metabolism / Review / site-directed mutagenesis / Structural Homology, Protein / Structure-Activity Relationship / virtual screening