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In silico identification, synthesis and biological evaluation of novel tetrazole inhibitors of MurB
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Hrast, Martina, Jukič, Marko, Patin, Delphine, Tod, Julie, Dowson, Christopher G., Roper, David I., Barreteau, Hélène and Gobec, Stanislav (2018) In silico identification, synthesis and biological evaluation of novel tetrazole inhibitors of MurB. Chemical Biology & Drug Design, 91 (6). pp. 1101-1112. doi:10.1111/cbdd.13172
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WRAP-In-silico-identification-synthesis-biological-evaluation-novel-tetrazole-inhibitors-MurB-Roper-2018.pdf - Accepted Version - Requires a PDF viewer. Download (996Kb) | Preview |
Official URL: http://dx.doi.org/10.1111/cbdd.13172
Abstract
In the context of antibacterial drug discovery resurgence, novel therapeutic targets and new compounds with alternative mechanisms of action are of paramount importance. We focused on UDP-N- acetylenolpyruvylglucosamine reductase (i.e. MurB), an underexploited target enzyme that is involved in early steps of bacterial peptidoglycan biosynthesis. On the basis of the recently reported crystal structure of MurB in complex with NADP+ , a pharmacopohore model was generated and used in a virtual screening campaign with combined structure-based and ligand-based approaches. In order to explore chemical space around hit compounds, further similarity search and organic synthesis was employed to obtain several compounds with micromolar IC50 values on MurB. The best inhibitors in the reported series of 5-substituted tetrazol-2-yl acetamides were compounds 13, 26 and 30 with IC50 values of 34, 28 and 25 µM, respectively. None of the reported compounds possessed in vitro antimicrobial activity against S. aureus and E. coli.
| Item Type: | Journal Article | ||||||||||||
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| Subjects: | Q Science > QR Microbiology R Medicine > RM Therapeutics. Pharmacology |
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| Divisions: | Faculty of Science > Life Sciences (2010- ) | ||||||||||||
| Library of Congress Subject Headings (LCSH): | Peptidoglycans, Biosynthesis, Tetrazoles , Tetrazoles--Synthesis, Antibacterial agents | ||||||||||||
| Journal or Publication Title: | Chemical Biology & Drug Design | ||||||||||||
| Publisher: | Wiley-Blackwell Publishing, Inc. | ||||||||||||
| ISSN: | 1747-0285 | ||||||||||||
| Official Date: | June 2018 | ||||||||||||
| Dates: |
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| Date of first compliant deposit: | 12 February 2018 | ||||||||||||
| Volume: | 91 | ||||||||||||
| Number: | 6 | ||||||||||||
| Page Range: | pp. 1101-1112 | ||||||||||||
| DOI: | 10.1111/cbdd.13172 | ||||||||||||
| Status: | Peer Reviewed | ||||||||||||
| Publication Status: | Published | ||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||||||
| RIOXX Funder/Project Grant: |
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