Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening

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

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Abstract

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.
Original languageEnglish
Pages (from-to)2452-2467
Number of pages16
JournalJournal of Medicinal Chemistry
Volume59
Issue number6
Early online date3 Mar 2016
DOIs
Publication statusPublished - 24 Mar 2016

Keywords

  • inhibitors
  • mitochondrial branched chain aminotransferase
  • BCATm
  • fragment screening
  • binding modes

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