10.1021/acs.jmedchem.5b00892.s001 John A. Christopher John A. Christopher Sarah J. Aves Sarah J. Aves Kirstie A. Bennett Kirstie A. Bennett Andrew S. Doré Andrew S. Doré James C. Errey James C. Errey Ali Jazayeri Ali Jazayeri Fiona H. Marshall Fiona H. Marshall Krzysztof Okrasa Krzysztof Okrasa Maria J. Serrano-Vega Maria J. Serrano-Vega Benjamin G. Tehan Benjamin G. Tehan Giselle R. Wiggin Giselle R. Wiggin Miles Congreve Miles Congreve Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu<sub>5</sub> Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile) American Chemical Society 2015 thermostabilized mGlu 5 receptor LE Class C GPCR mGlu 5 receptor complexed mGlu 5 HTL ligand efficiency 2015-08-27 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Fragment_and_Structure_Based_Drug_Discovery_for_a_Class_C_GPCR_Discovery_of_the_mGlu_sub_5_sub_Negative_Allosteric_Modulator_HTL14242_3_Chloro_5_6_5_fluoropyridin_2_yl_pyrimidin_4_yl_benzonitrile_/2136946 Fragment screening of a thermostabilized mGlu<sub>5</sub> receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit <b>5</b>. Subsequent optimization using structure-based drug discovery methods led to the selection of <b>25</b>, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu<sub>5</sub> receptor complexed with <b>25</b> and another molecule in the series, <b>14</b>, were determined at resolutions of 2.6 and 3.1 Å, respectively.