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

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• 作者：Jennifer A. Borthwick ; Nicolas Ancellin ; Sophie M. Bertrand ; Ryan P. Bingham ; Paul S. Carter ; Chun-wa Chung ; Ian Churcher ; Nerina Dodic ; Charlène Fournier ; Peter L. Francis ; Andrew Hobbs ; Craig Jamieson ; Stephen D. Pickett ; Sarah E. Smith ; Donald O’N. Somers ; Claus Spitzfaden ; Colin J. Suckling ; Robert J. Young
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2452-2467
• 全文大小：827K
• ISSN：1520-4804

文摘

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 (T_m), 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.