title: Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.
abstract: Following insights from recent crystal structures of the muscarinic acetylcholine receptor, binding modes of Positive Allosteric Modulators (PAMs) were predicted under the assumption that PAMs should bind to the extracellular surface of the active state. A series of well-characterized PAMs for adenosine (A1R, A2AR, A3R) and muscarinic acetylcholine (M1R, M5R) receptors were modeled using both rigid and flexible receptor CHARMM-based molecular docking. Studies of adenosine receptors investigated the molecular basis of the probe-dependence of PAM activity by modeling in complex with specific agonist radioligands. Consensus binding modes map common pharmacophore features of several chemical series to specific binding interactions. These models provide a rationalization of how PAM binding slows agonist radioligand dissociation kinetics. M1R PAMs were predicted to bind in the analogous M2R PAM LY2119620 binding site. The M5R NAM (ML-375) was predicted to bind in the PAM (ML-380) binding site with a unique induced-fit receptor conformation. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, 901 Walnut St. Suite 918, Philadelphia, Pennsylvania, 19170.
authors.forename: Leon A
authors.initials: LA
authors.lastname: Sakkal
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, 901 Walnut St. Suite 918, Philadelphia, Pennsylvania, 19170.
authors.forename: Kyle Z
authors.initials: KZ
authors.lastname: Rajkowski
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, 901 Walnut St. Suite 918, Philadelphia, Pennsylvania, 19170.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Armen
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000495:Allosteric Site / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D018721:Muscarinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018721:Muscarinic Agonists; D058906:Purinergic P1 Receptor Agonists; D011976:Receptors, Muscarinic; D018047:Receptors, Purinergic P1
keywords: Cl-IB-MECA; LUF6000; MRS-542; inosine; ischemic