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J Med Chem. 2016 Mar 24;59(6):2452-67. doi: 10.1021/acs.jmedchem.5b01607. Epub 2016 Mar 16.

Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads with Varying Binding Modes Identified by Fragment Screening.

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Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
Les Ulis, Centre de Recherche, GlaxoSmithKline R&D , 25,27 Avenue du Qu├ębec, 91140 Villebon sur Yvette, France.


Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility.

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