Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

Ricky Cain, Ramya Salimraj, Avinash Punekar, Dom Belini, Colin W. G. Fishwick, Lloyd Czaplewski, David J. Scott, Gemma Harris, Christopher G. Dowson, Adrian J. Lloyd, David I. Roper (Lead / Corresponding author)

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)9703-9717
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number21
Early online date18 Oct 2019
DOIs
Publication statusPublished - 18 Oct 2019

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    Cain, R., Salimraj, R., Punekar, A., Belini, D., Fishwick, C. W. G., Czaplewski, L., Scott, D. J., Harris, G., Dowson, C. G., Lloyd, A. J., & Roper, D. I. (2019). Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase. Journal of Medicinal Chemistry, 62(21), 9703-9717. https://doi.org/10.1021/acs.jmedchem.9b01131