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.