Structural Probing and Molecular Modeling of the A(3) Adenosine Receptor: A Focus on Agonist Binding

Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A(1), A(2A), A(2B) and A(3), which belong to the G protein-coupled receptor (GPCR) superfamily. The human A(3)AR (hA(3)AR) subtype is implicated in several cytoprotective functions. Therefore, hA(3)AR 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 A(3)AR 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 A(3)AR and discuss the challenges associated with an accurate prediction of the receptor extracellular vestibule through homology modeling from the available X-ray templates.