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

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• 作者：Min Teng ; Mark T. Hilgers ; Mark L. Cunningham ; Allen Borchardt ; Jeffrey B. Locke ; Sunny Abraham ; Gregory Haley ; Bryan P. Kwan ; Courtney Hall ; Grayson W. Hough ; Karen J. Shaw ; John Finn
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 28, 2013
• 年：2013
• 卷：56
• 期：4
• 页码：1748-1760
• 全文大小：668K
• 年卷期：v.56,no.4(February 28, 2013)
• ISSN：1520-4804

文摘

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.