Discovery of Novel Acetohydroxyacid Synthase Inhibitors as Active Agents against Mycobacterium tuberculosis by Virtual Screening and Bioassay

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• 作者：Di Wang ; Xuelian Zhu ; Changjun Cui ; Mei Dong ; Hualiang Jiang ; Zhengming Li ; Zhen Liu ; Weiliang Zhu ; Jian-Guo Wang
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2013
• 出版时间：February 25, 2013
• 年：2013
• 卷：53
• 期：2
• 页码：343-353
• 全文大小：516K
• 年卷期：v.53,no.2(February 25, 2013)
• ISSN：1549-960X

文摘

Acetohydroxyacid synthase (AHAS) has been regarded as a promising drug target against Mycobacterium tuberculosis (MTB) as it catalyzes the biosynthesis of branched-chain amino acids. In this study, 23 novel AHAS inhibitors were identified through molecular docking followed by similarity search. The determined IC₅₀ values range from 0.385 卤 0.026 渭M to >200 渭M against bacterium AHAS. Five of the identified compounds show significant in vitro activity against H37Rv strains (MICs in the range of 2.5鈥?0 mg/L) and clinical MTB strains, including MDR and XDR isolates. More impressively, compounds 5 and 7 can enhance the killing ability against macrophages infected pathogen remarkably. This study suggests our discovered inhibitors can be further developed as novel anti-MTB therapeutics targeting AHAS.