Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)
Copyright policy )Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)
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.
- University of Hertfordshire United Kingdom
Models, Molecular, Pyridines, Receptor, Metabotropic Glutamate 5, Molecular Conformation, Ligands, Rats, Receptors, G-Protein-Coupled, Structure-Activity Relationship, Dogs, HEK293 Cells, Pyrimidines, Allosteric Regulation, Drug Design, Drug Discovery, Animals, Humans, Caco-2 Cells
Models, Molecular, Pyridines, Receptor, Metabotropic Glutamate 5, Molecular Conformation, Ligands, Rats, Receptors, G-Protein-Coupled, Structure-Activity Relationship, Dogs, HEK293 Cells, Pyrimidines, Allosteric Regulation, Drug Design, Drug Discovery, Animals, Humans, Caco-2 Cells
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