title: 7TM X-ray structures for class C GPCRs as new drug-discovery tools. 1. mGluR5.
abstract: We illustrate, with a focus on mGluR5, how the recently published, first X-ray structures of mGluR 7TM domains, specifically those of mGluR1 and mGluR5 complexed with negative allosteric modulators (NAMs), will begin to influence ligand- (e.g., drug- or sweetener-) discovery efforts involving class C GPCRs. With an extensive docking study allowing full ligand flexibility and full side chain flexibility of all residues in the ligand-binding cavity, we have predicted and analyzed the binding modes of a variety of structurally diverse mGluR5 NAM ligands, showing how the X-ray structures serve to effectively rationalize each ligand's binding characteristics. We demonstrated that the features that are inherent in our earlier overlay model are preserved in the protein structure-based docking models. We identified structurally diverse compounds, which potentially act as mGluR NAMs, and revealed binding-site differences by performing high-throughput docking using a database of approximately six million structures of commercially available compounds and the mGluR1 and mGluR5 X-ray structures. By comparing the 7TM domains of the mGluR5 and mGluR1 X-rays structures, we identified selectivity factors within group I of the mGluRs. Similarly, using homology models that we built for mGluR2 and mGluR4, we have identified the factors leading to the selectivity between group I and groups II and III for ligands occupying the deepest portion of the mGluR5 binding cavity. Finally, we have proposed a structure-based explanation of the pharmacological switching within a set of positive allosteric modulators (PAMs) and their corresponding, very close NAM analogs.
authors.affiliation: Stevens Institute of Technology, Center for Healthcare Innovation, 507 River Street, Hoboken, NJ, USA; 3D-2Drug, PO Box 184, Fair Lawn, NJ, USA. Electronic address: Sid.Topiol@gmail.com.
authors.forename: Sid
authors.initials: S
authors.lastname: Topiol
authors.affiliation: Stevens Institute of Technology, Center for Healthcare Innovation, 507 River Street, Hoboken, NJ, USA; 3D-2Drug, PO Box 184, Fair Lawn, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Sabio
mesh_terms: D001549:Benzamides / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D000072417:Protein Domains; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry; D014227:Triazines / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry
chemical_list: C000613475:3-chloro-4-fluoro-5-(6-(1H-pyrazol-1-yl)pyrimidin-4-yl)benzonitrile; C000602649:3-chloro-5-(6-(5-fluoropyridin-2-yl)pyrimidin-4-yl)benzonitrile; C560416:4-fluoro-N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N-methylbenzamide; D001549:Benzamides; D007211:Indoles; D008024:Ligands; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D064529:Receptor, Metabotropic Glutamate 5; D013844:Thiazoles; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C121465:6-methyl-2-(phenylethynyl)pyridine; C581397:mavoglurant
keywords: Computer-aided drug discovery; Docking; Mavoglurant; Metabotropic glutamate receptors (mGluRs); Negative allosteric modulators (NAMs); Positive allosteric modulators (PAMs); Structure-based drug design; X-ray structure