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)
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Abstract
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