5i60

Publication Abstract from PubMed

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.

Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads with Varying Binding Modes Identified by Fragment Screening.,Borthwick JA, Ancellin N, Bertrand SM, Bingham RP, Carter PS, Chung CW, Churcher I, Dodic N, Fournier C, Francis PL, Hobbs A, Jamieson C, Pickett SD, Smith SE, Somers DO, Spitzfaden C, Suckling CJ, Young RJ J Med Chem. 2016 Mar 24;59(6):2452-67. doi: 10.1021/acs.jmedchem.5b01607. Epub, 2016 Mar 16. PMID:26938474^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.