Identification of Bacteria-Selective Threonyl-tRNA Synthetase Substrate Inhibitors by Structure-Based Design

A series of potent and bacteria-selective threonyl-tRNA synthetase (ThrRS) inhibitors have been identified using structure-based drug design. These compounds occupied the substrate binding site of ThrRS and showed excellent binding affinities for all of the bacterial orthologues tested. Some of the...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-02, Vol.56 (4), p.1748-1760
Main Authors: Teng, Min, Hilgers, Mark T, Cunningham, Mark L, Borchardt, Allen, Locke, Jeffrey B, Abraham, Sunny, Haley, Gregory, Kwan, Bryan P, Hall, Courtney, Hough, Grayson W, Shaw, Karen J, Finn, John
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - chemistry
Binding Sites
Burkholderia - drug effects
Crystallography, X-Ray
Drug Resistance, Bacterial
Escherichia coli - drug effects
Escherichia coli - genetics
Escherichia coli Proteins - antagonists & inhibitors
Escherichia coli Proteins - chemistry
Haemophilus influenzae - drug effects
Humans
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Mutation
Protein Binding
Quinazolines - chemical synthesis
Quinazolines - chemistry
Quinazolines - pharmacology
Stereoisomerism
Structure-Activity Relationship
Substrate Specificity
Threonine-tRNA Ligase - antagonists & inhibitors
Threonine-tRNA Ligase - chemistry
Yersinia pestis - drug effects
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Summary:A series of potent and bacteria-selective threonyl-tRNA synthetase (ThrRS) inhibitors have been identified using structure-based drug design. These compounds occupied the substrate binding site of ThrRS and showed excellent binding affinities for all of the bacterial orthologues tested. Some of the compounds displayed greatly improved bacterial selectivity. Key residues responsible for potency and bacteria/human ThrRS selectivity have been identified. Antimicrobial activity has been achieved against wild-type Haemophilus influenzae and efflux-deficient mutants of Escherichia coli and Burkholderia thailandensis.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm301756m