Discovery of novel acetohydroxyacid synthase inhibitors as active agents against Mycobacterium tuberculosis by virtual screening and bioassay.

Di Wang, Xuelian Zhu, Changjun Cui, Mei Dong, Hualiang Jiang, Zhengming Li, Zhen Liu, Weiliang Zhu, Jian-Guo Wang

Department of Clinical Laboratory, 309 Hospital of Chinese People's Liberation Army, Beijing 100091, China.

Journal of chemical information and modeling 2013 Feb 25

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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 IC(50) values range from 0.385 ± 0.026 μM to >200 μM against bacterium AHAS. Five of the identified compounds show significant in vitro activity against H37Rv strains (MICs in the range of 2.5-80 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.

Citation

Di Wang, Xuelian Zhu, Changjun Cui, Mei Dong, Hualiang Jiang, Zhengming Li, Zhen Liu, Weiliang Zhu, Jian-Guo Wang. Discovery of novel acetohydroxyacid synthase inhibitors as active agents against Mycobacterium tuberculosis by virtual screening and bioassay. Journal of chemical information and modeling. 2013 Feb 25;53(2):343-53