Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu₅ Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

Abstract

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.

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

“…174,175 Recent mGlu 5 cocrystal structures of the 7TM domains with negative allosteric modulators observed Y658, S808 and W784 hydrogen bonding with a water molecule. 176,177 These data suggest that changes in the water network and/or the stability of water-receptor interactions can also contribute to cooperativity mode switches, instead of, or in addition to, direct ligand-receptor interactions. In the mGlu 1 7TM cocrystal structure with FITM (a negative allosteric modulator), however, no crystallographic waters were present within the allosteric modulator binding pocket.…”

Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor

“…As with the phenylalkylamines, docking Structure-function analysis of calcium receptor allostery was performed by extensive conformational sampling of the ligand and pocket residue side-chains; however, in contrast to the phenylalkylamines, this resulted in several plausible poses of the compound differing by its orientation inside the pocket and by rotamer states of phenylalanine residues. Thus, in an attempt to further refine our docking studies, we took advantage of the publication of two new mGlu 5 crystal structures in complex with two novel compounds that bind in a similar location to our predicted AC-265347 binding site [55]. In fact, homologous residues to those where mutations alter AC-265347 pK B (W818 6.50 , F821 6.53 and A844 7.39 ) comprise the binding site of the novel mGlu 5 allosteric ligands [55].…”

“…Thus, in an attempt to further refine our docking studies, we took advantage of the publication of two new mGlu 5 crystal structures in complex with two novel compounds that bind in a similar location to our predicted AC-265347 binding site [55]. In fact, homologous residues to those where mutations alter AC-265347 pK B (W818 6.50 , F821 6.53 and A844 7.39 ) comprise the binding site of the novel mGlu 5 allosteric ligands [55]. Homology modeling and docking were subsequently performed using all available structures of homologous proteins, including PDB: 4OR2 (GRM1), 4OO9, 5CGC and 5CGD (GRM5).…”

Integrated In Silico Fragment-Based Drug Design: Case Study with Allosteric Modulators on Metabotropic Glutamate Receptor 5

“…The first model (PDB entry: 4OO9; resolution, 2.6 Å; method, X-ray diffraction) (16) was in complex with the negative allosteric modulator, mavoglurant. The second model (PDB entry: 5CGD; resolution, 2.6 Å; method, X-ray diffraction) (37) was in complex with the negative allosteric modulator, HTL14242. The structures of mGlu 5 were downloaded from the Protein Data Bank (PDB).…”