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

Research output: Contribution to journalArticle

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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

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X Ray Crystallography
Sexually Transmitted Diseases
Solubility
Screening
Hot Temperature
X-Rays
Ligands
X ray crystallography
Assays
Nuclear magnetic resonance
X rays
Molecules
branched-chain-amino-acid transaminase

Keywords

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

Cite this

Borthwick, Jennifer A. ; Ancellin, Nicolas ; Bertrand, Sophie M. ; Bingham, Ryan P. ; Carter, Paul S. ; Chung, Chun-wa ; Churcher, Ian ; Dodic, Nerina ; Fournier, Charlène ; Francis, Peter L. ; Hobbs, Andrew ; Jamieson, Craig ; Pickett, Stephen D. ; Smith, Sarah E. ; Somers, Donald O'N. ; Spitzfaden, Claus ; Suckling, Colin J. ; Young, Robert J. / Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 6. pp. 2452-2467.
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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.",
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note = "This document is the unedited Author's version of a Submitted Work that was subsequently accepted for publication in Journal of Medicinal Chemistry, copyright {\circledC} 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.",
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Borthwick, JA, Ancellin, N, Bertrand, SM, Bingham, RP, Carter, PS, Chung, C, Churcher, I, Dodic, N, Fournier, C, Francis, PL, Hobbs, A, Jamieson, C, Pickett, SD, Smith, SE, Somers, DON, Spitzfaden, C, Suckling, CJ & Young, RJ 2016, 'Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening', Journal of Medicinal Chemistry, vol. 59, no. 6, pp. 2452-2467. https://doi.org/10.1021/acs.jmedchem.5b01607

Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening. / Borthwick, Jennifer A.; Ancellin, Nicolas; Bertrand, Sophie M.; Bingham, Ryan P.; Carter, Paul S.; Chung, Chun-wa; Churcher, Ian; Dodic, Nerina; Fournier, Charlène; Francis, Peter L.; Hobbs, Andrew; Jamieson, Craig; Pickett, Stephen D.; Smith, Sarah E.; Somers, Donald O'N.; Spitzfaden, Claus; Suckling, Colin J.; Young, Robert J.

In: Journal of Medicinal Chemistry, Vol. 59, No. 6, 24.03.2016, p. 2452-2467.

Research output: Contribution to journalArticle

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T1 - Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening

AU - Borthwick, Jennifer A.

AU - Ancellin, Nicolas

AU - Bertrand, Sophie M.

AU - Bingham, Ryan P.

AU - Carter, Paul S.

AU - Chung, Chun-wa

AU - Churcher, Ian

AU - Dodic, Nerina

AU - Fournier, Charlène

AU - Francis, Peter L.

AU - Hobbs, Andrew

AU - Jamieson, Craig

AU - Pickett, Stephen D.

AU - Smith, Sarah E.

AU - Somers, Donald O'N.

AU - Spitzfaden, Claus

AU - Suckling, Colin J.

AU - Young, Robert J.

N1 - 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.

PY - 2016/3/24

Y1 - 2016/3/24

N2 - 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.

AB - 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.

KW - inhibitors

KW - mitochondrial branched chain aminotransferase

KW - BCATm

KW - fragment screening

KW - binding modes

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U2 - 10.1021/acs.jmedchem.5b01607

DO - 10.1021/acs.jmedchem.5b01607

M3 - Article

VL - 59

SP - 2452

EP - 2467

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 6

ER -