Structure-Based Approaches to Ligands for G-Protein-Coupled Adenosine and P2Y Receptors, from Small Molecules to Nanoconjugates

Adenosine receptor (ARs) and P2Y receptors (P2YRs) that respond to extracellular nucleosides/nucleotides are associated with new directions for therapeutics. The X-ray structures of the A2AAR complexes with agonists and antagonists are examined in relationship to the G-protein-coupled receptor (GPCR) superfamily and applied to drug discovery. Much of the data on AR ligand structure from early SAR studies now are explainable from the A2AAR X-ray crystallography. The ligand-receptor interactions in related GPCR complexes can be identified by means of modeling approaches, e.g., molecular docking. Thus, molecular recognition in binding and activation processes has been studied effectively using homology modeling and applied to ligand design. Virtual screening has yielded new nonnucleoside AR antagonists, and existing ligands have been improved with knowledge of the receptor interactions. New agonists are being explored for central nervous system and peripheral therapeutics based on in vivo activity, such as chronic neuropathic pain. Ligands for receptors more distantly related to the X-ray template, i.e., P2YRs, have been introduced and are mainly used as pharmacological tools for elucidating the physiological role of extracellular nucleotides. Other ligand tools for drug discovery include fluorescent probes, radioactive probes, multivalent probes, and functionalized nanoparticles.