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Issue 2, 2017
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NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors

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Abstract

There are no clinically useful inhibitors of metallo-β-lactamases (MBLs), which are a growing problem because they hydrolyse almost all β-lactam antibacterials. Inhibition by most reported MBL inhibitors involves zinc ion chelation. A structure-based virtual screening approach combined with NMR filtering led to the identification of inhibitors of the clinically relevant Verona Integron-encoded MBL (VIM)-2. Crystallographic analyses reveal a new mode of MBL inhibition involving binding adjacent to the active site zinc ions, but which does not involve metal chelation. The results will aid efforts to develop new types of clinically useful inhibitors targeting MBLs/MBL-fold metallo-enzymes involved in antibacterial and anticancer drug resistance.

Graphical abstract: NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors

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Publication details

The article was received on 10 Oct 2016, accepted on 13 Dec 2016 and first published on 14 Dec 2016


Article type: Edge Article
DOI: 10.1039/C6SC04524C
Chem. Sci., 2017,8, 928-937
  • Open access: Creative Commons BY license
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    NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors

    G. Li, M. I. Abboud, J. Brem, H. Someya, C. T. Lohans, S. Yang, J. Spencer, D. W. Wareham, M. A. McDonough and C. J. Schofield, Chem. Sci., 2017, 8, 928
    DOI: 10.1039/C6SC04524C

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