John Daly Lecture: Structure-guided Drug Design for Adenosine and P2Y Receptors☆

摘要: We establish structure activity relationships of extracellular nucleosides and nucleotides at G protein-coupled receptors (GPCRs), e.g. adenosine (ARs) P2Y (P2YRs), respectively. synthesize selective agents for use as pharmacological probes potential therapeutic (e.g. A3AR agonists neuropathic pain). Detailed structural information derived from the X-ray crystallographic structures within these families enables design novel ligands, guides modification known antagonists, helps predict polypharmacology. Structures were recently reported P2Y12 receptor (P2Y12R), an anti-thrombotic target. Comparison agonist-bound antagonist-bound P2Y12R indicates unprecedented plasticity in outer portions transmembrane (TM) domains loops. Nonphosphate-containing ligands P2YRs, such P2Y14R antagonist PPTN, are desired bioavailability increased stability. Also, A2AAR effectively applied to homology modeling closely related A1AR A3AR, which not yet crystallized. Conformational constraint normally flexible ribose with bicyclic analogues ligand selectivity. rigid agonist congeners allows exploration interaction specific regions nucleoside target off-target GPCRs, biogenic amine receptors. Molecular predicts TM2 accommodate highly rigidified ligands. Novel fluorescent derivatives high affinity GPCR useful tool compounds characterization their oligomeric assemblies. Fluorescent GPCRs living cells by flow cytometry other methods. Thus, 3D knowledge binding activation facilitates drug discovery.