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Li GB, Abboud MI, Brem J, et al. NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors. Chem Sci. 2016;8(2):928-937doi: 10.1039/c6sc04524c.
Li, G. B., Abboud, M. I., Brem, J., Someya, H., Lohans, C. T., Yang, S. Y., Spencer, J., Wareham, D. W., McDonough, M. A., & Schofield, C. J. (2017). NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors. Chemical science, 8(2), 928-937. https://doi.org/10.1039/c6sc04524c
Li, Guo-Bo, et al. "NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors." Chemical science vol. 8,2 (2017): 928-937. doi: https://doi.org/10.1039/c6sc04524c
Li GB, Abboud MI, Brem J, Someya H, Lohans CT, Yang SY, Spencer J, Wareham DW, McDonough MA, Schofield CJ. NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors. Chem Sci. 2017 Feb 01;8(2):928-937. doi: 10.1039/c6sc04524c. Epub 2016 Dec 14. PMID: 28451231; PMCID: PMC5369532.
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Chem Sci. 2017 Feb 01;8(2):928-937. doi: 10.1039/c6sc04524c. Epub 2016 Dec 14.

NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors.

Chemical science

Guo-Bo Li, Martine I Abboud, Jürgen Brem, Hidenori Someya, Christopher T Lohans, Sheng-Yong Yang, James Spencer, David W Wareham, Michael A McDonough, Christopher J Schofield

Affiliations

  1. Department of Chemistry , University of Oxford , 12 Mansfield Road , Oxford , OX1 3TA , UK . Email: [email protected] ; Email: [email protected].
  2. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education , West China School of Pharmacy , Sichuan University , Chengdu , 610041 , China.
  3. Medicinal Chemistry Research Laboratories , New Drug Research Division , Otsuka Pharmaceutical Co., Ltd. , 463-10 Kagasuno, Kawauchi-cho , Tokushima 771-0192 , Japan.
  4. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy , West China Hospital , West China Medical School , Sichuan University , Sichuan 610041 , China.
  5. School of Cellular and Molecular Medicine , Biomedical Sciences Building , University of Bristol , Bristol BS8 1TD , UK.
  6. Antimicrobial Research Group , Barts & The London School of Medicine and Dentistry , Queen Mary University of London , London , E1 2AT , UK.

PMID: 28451231 PMCID: PMC5369532 DOI: 10.1039/c6sc04524c

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.

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