Sunday , February 8 , 2015 95 a Membrane Receptors and Signal Transduction

479-Pos Board B259 Activation and Drug Design of a Muscarinic G-Protein Coupled Receptor Yinglong Miao1, J. Andrew McCammon1,2. Howard Hughes Medical Institute/University of California at San Diego, La Jolla, CA, USA, Pharmacology, Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, USA. The M2 muscarinic acetylcholine receptor is a key G-protein coupled receptor (GPCR) that regulates the human heart rate and contractile forces of cardiomyocytes, and is thus targeted for treating many heart diseases. Here, we have performed long-timescale accelerated molecular dynamics (aMD) simulations and captured activation of theM2muscarinic receptor at an atomistic level(1). The receptor activation is characterized by large-scale structural rearrangements of the transmembrane helices and conformational changes in the inter-helical salt bridge and hydrogen bond interactions(1, 2). Furthermore, using the aMD simulationderived structural ensembles that account for the receptor flexibility,wehavemapped the receptor surface for druggable allosteric sites(3) and then targeted the extracellular vestibule for designing allosteric modulators. Retrospective docking of known ligands is first carried out to validate the simulation receptor ensembles, followed by prospective docking to predict new allosteric modulators from the National Cancer Institute (NCI) compound library. The computationally selected compoundswill be testedusing experimental bindingand functional assays,which may allow us to discover selective allosteric drugs of theM2muscarinic receptor. References 1. Miao Y, Nichols SE, Gasper PM, Metzger VT, McCammon JA (2013) Activation and dynamic network of the M2muscarinic receptor. Proc Natl Acad Sci U S A 110(27):10982-10987. 2. Miao Y, Nichols SE, McCammon JA (2014) Free Energy Landscape of G-Protein Coupled Receptors, Explored by Accelerated Molecular Dynamics. Phys Chem Chem Phys 16(14):6398 6406. 3. Miao Y, Nichols SE, McCammon JA (2013) Mapping of Allosteric Druggable Sites in Activation-Associated Conformers of the M2 Muscarinic Receptor. Chem Biol Drug Des 83(2):237-246.