title: Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads with Varying Binding Modes Identified by Fragment Screening.
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.
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.|Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Borthwick
authors.affiliation: Les Ulis, Centre de Recherche, GlaxoSmithKline R&D , 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ancellin
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.|Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Bertrand
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Bingham
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Carter
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Ian
authors.initials: I
authors.lastname: Churcher
authors.affiliation: Les Ulis, Centre de Recherche, GlaxoSmithKline R&D , 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
authors.forename: Nerina
authors.initials: N
authors.lastname: Dodic
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Charlène
authors.initials: C
authors.lastname: Fournier
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Francis
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hobbs
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Craig
authors.initials: C
authors.lastname: Jamieson
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Pickett
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Smith
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Donald O'N
authors.initials: DO
authors.lastname: Somers
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Claus
authors.initials: C
authors.lastname: Spitzfaden
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Suckling
authors.affiliation: Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D018360:Crystallography, X-Ray; D057166:High-Throughput Screening Assays; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000201:enzymology*; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D000637:Transaminases / Q000037:antagonists & inhibitors*
chemical_list: D010446:Peptide Fragments; D000637:Transaminases