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Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase
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Cain, Ricky, Salimraj, Ramya, Punekar, Avinash S., Bellini, Dom, Fishwick, Colin W. G., Czaplewski, Lloyd, Scott, David J., Harris, Gemma, Dowson, Christopher G., Lloyd, Adrian J. and Roper, David I. (2019) Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase. Journal of Medicinal Chemistry, 62 (21). pp. 9703-9717. doi:10.1021/acs.jmedchem.9b01131 ISSN 0022-2623.
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WRAP-structure-guided-enhancement-selectivity-chemical-probe-inhibitors-targeting-bacterial-seryl-tRNA-synthetase-Roper-2019.pdf - Accepted Version - Requires a PDF viewer. Download (2406Kb) | Preview |
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Official URL: http://dx.doi.org/10.1021/acs.jmedchem.9b01131
Abstract
Aminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high-resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than 2 orders of magnitude compared to their human homologue, demonstrating a route to the selective chemical inhibition of these bacterial targets.
| Item Type: | Journal Article | ||||||||||||
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| Subjects: | Q Science > QP Physiology | ||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||||||
| Library of Congress Subject Headings (LCSH): | Biochemistry, Aminoacyl-tRNA synthetases, Proteins -- Synthesis, Aminoacyl-tRNA, Escherichia coli | ||||||||||||
| Journal or Publication Title: | Journal of Medicinal Chemistry | ||||||||||||
| Publisher: | American Chemical Society | ||||||||||||
| ISSN: | 0022-2623 | ||||||||||||
| Official Date: | 14 November 2019 | ||||||||||||
| Dates: |
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| Volume: | 62 | ||||||||||||
| Number: | 21 | ||||||||||||
| Page Range: | pp. 9703-9717 | ||||||||||||
| DOI: | 10.1021/acs.jmedchem.9b01131 | ||||||||||||
| Status: | Peer Reviewed | ||||||||||||
| Publication Status: | Published | ||||||||||||
| Reuse Statement (publisher, data, author rights): | This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.9b01131 | ||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||||||
| Date of first compliant deposit: | 19 November 2019 | ||||||||||||
| Date of first compliant Open Access: | 18 October 2020 | ||||||||||||
| RIOXX Funder/Project Grant: |
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