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

Borthwick, Jennifer A. and Ancellin, Nicolas and Bertrand, Sophie M. and Bingham, Ryan P. and Carter, Paul S. and Chung, Chun-wa and Churcher, Ian and Dodic, Nerina and Fournier, Charlène and Francis, Peter L. and Hobbs, Andrew and Jamieson, Craig and Pickett, Stephen D. and Smith, Sarah E. and Somers, Donald O'N. and Spitzfaden, Claus and Suckling, Colin J. and Young, Robert J. (2016) Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening. Journal of Medicinal Chemistry, 59 (6). pp. 2452-2467. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.5b01607)

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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.

  • Item type:Article
    ID code:55944
    Dates:
    Date
    Event
    24 March 2016
    Published
    3 March 2016
    Published Online
    3 March 2016
    Accepted
    Notes:This document is the unedited Author's version of a Submitted Work that was subsequently accepted for publication in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01607.
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:18 Mar 2016 12:20
    Last modified:08 Apr 2024 22:51
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/55944
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