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

Publication date: Available online 16 October 2014 Source:Computational and Structural Biotechnology Journal Author(s): Kenneth A. Jacobson , Zhan-Guo Gao , Silvia Paoletta , Evgeny Kiselev , Saibal Chakraborty , P. Suresh Jayasekara , Ramachandran Balasubramanian , Dilip K. Tosh We establish structure activity relationships of extracellular nucleosides and nucleotides at G protein-coupled receptors (GPCRs), e.g. adenosine receptors (ARs) and P2Y receptors (P2YRs), respectively. We synthesize selective agents for use as pharmacological probes and potential therapeutic agents (e.g. A3AR agonists for neuropathic pain). Detailed structural information derived from the X-ray crystallographic structures within these families enables the design of novel ligands, guides modification of known agonists and antagonists, and helps predict polypharmacology. Structures were recently reported for the P2Y12 receptor (P2Y12R), an anti-thrombotic target. Comparison of agonist-bound and antagonist-bound P2Y12R indicates unprecedented structural plasticity in the outer portions of the transmembrane (TM) domains and the extracellular loops. Nonphosphate-containing ligands of the P2YRs, such as the selective P2Y14R antagonist PPTN, are desired for bioavailability and increased stability. Also, A2AAR structures are effectively applied to homology modeling of closely related A1AR and A3AR, which are not yet crystallized. Conformational constraint of normally flexible ribose with bicycli...
Source: Computational and Structural Biotechnology Journal - Category: Biotechnology Source Type: research