mavoglurant and 3-chloro-5-(6-(5-fluoropyridin-2-yl)pyrimidin-4-yl)benzonitrile

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.

Topics: Benzamides; Binding Sites; Crystallography, X-Ray; Drug Discovery; Indoles; Ligands; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Protein Domains; Pyrazoles; Pyridines; Pyrimidines; Receptor, Metabotropic Glutamate 5; Thiazoles; Triazines; Triazoles

Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 Å, respectively.

Topics: Allosteric Regulation; Animals; Caco-2 Cells; Dogs; Drug Design; Drug Discovery; HEK293 Cells; Humans; Ligands; Models, Molecular; Molecular Conformation; Pyridines; Pyrimidines; Rats; Receptor, Metabotropic Glutamate 5; Receptors, G-Protein-Coupled; Structure-Activity Relationship