Structure-Guided Design of Novel Thiazolidine Inhibitors of O-Acetyl Serine Sulfhydrylase from Mycobacterium tuberculosis

详细信息    查看全文

• 作者：脰mer Poyraz ; Variam Ullas Jeankumar ; Shalini Saxena ; Robert Schnell ; Martin Haraldsson ; Perumal Yogeeswari ; Dharmarajan Sriram ; Gunter Schneider
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 22, 2013
• 年：2013
• 卷：56
• 期：16
• 页码：6457-6466
• 全文大小：374K
• 年卷期：v.56,no.16(August 22, 2013)
• ISSN：1520-4804

文摘

The cysteine biosynthetic pathway is absent in humans but essential in microbial pathogens, suggesting that it provides potential targets for the development of novel antibacterial compounds. CysK1 is a pyridoxalphosphate-dependent O-acetyl sulfhydrylase, which catalyzes the formation of l-cysteine from O-acetyl serine and hydrogen sulfide. Here we report nanomolar thiazolidine inhibitors of Mycobacterium tuberculosis CysK1 developed by rational inhibitor design. The thiazolidine compounds were discovered using the crystal structure of a CysK1鈥損eptide inhibitor complex as template. Pharmacophore modeling and subsequent in vitro screening resulted in an initial hit compound 2 (IC₅₀ of 103.8 nM), which was subsequently optimized by a combination of protein crystallography, modeling, and synthetic chemistry. Hit expansion of 2 by chemical synthesis led to improved thiazolidine inhibitors with an IC₅₀ value of 19 nM for the best compound, a 150-fold higher potency than the natural peptide inhibitor (IC₅₀ 2.9 渭M).