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

2016; American Chemical Society; Volume: 59; Issue: 6 Linguagem: Inglês

10.1021/acs.jmedchem.5b01607

1520-4804

Alan D. Borthwick, Nicolas Ancellin, Sophie M. Bertrand, Ryan P. Bingham, Paul S. Carter, Chun‐wa Chung, Ian Churcher, Nérina Dodic, Charlène Fournier, Peter Francis, Andrew N. Hobbs, Craig Jamieson, Stephen D. Pickett, Sarah E. Smith, D.O. Somers, Claus Spitzfaden, Colin J. Suckling, Robert J. Young,

ATP Synthase and ATPases Research

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.