NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors
<p>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...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Published: |
Royal Society of Chemistry
2017
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| _version_ | 1797054638628798464 |
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| author | Li, G Abboud, M Brem, J Someya, H Lohans, C Yang, S Spencer, J Wareham, D McDonough, M Schofield, C |
| author_facet | Li, G Abboud, M Brem, J Someya, H Lohans, C Yang, S Spencer, J Wareham, D McDonough, M Schofield, C |
| author_sort | Li, G |
| collection | OXFORD |
| description | <p>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.</p> |
| first_indexed | 2024-03-06T19:00:02Z |
| format | Journal article |
| id | oxford-uuid:13353036-e4e0-403f-9576-a1278a98a11a |
| institution | University of Oxford |
| last_indexed | 2024-03-06T19:00:02Z |
| publishDate | 2017 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | oxford-uuid:13353036-e4e0-403f-9576-a1278a98a11a2022-03-26T10:12:35ZNMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitorsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:13353036-e4e0-403f-9576-a1278a98a11aSymplectic Elements at OxfordRoyal Society of Chemistry2017Li, GAbboud, MBrem, JSomeya, HLohans, CYang, SSpencer, JWareham, DMcDonough, MSchofield, C<p>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.</p> |
| spellingShingle | Li, G Abboud, M Brem, J Someya, H Lohans, C Yang, S Spencer, J Wareham, D McDonough, M Schofield, C NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors |
| title | NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors |
| title_full | NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors |
| title_fullStr | NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors |
| title_full_unstemmed | NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors |
| title_short | NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors |
| title_sort | nmr filtered virtual screening leads to non metal chelating metallo β lactamase inhibitors |
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