基于吲哚-3-甘油磷酸合成酶结构的新型抗结核药物的筛选  

Screening of novel inhibitors of indole-3-glycerol phosphate synthase from Mycobacterium tuberculosis

作　　者：周涛[1,2] 王菲菲[3] 黄强[4] 王洪海[4] 沈洪波[2] 

机构地区：[1]上海大学生命科学学院,上海200444 [2]中国科学院上海巴斯德研究所,上海200031 [3]复旦大学基础医学院病原生物学系,上海200032 [4]复旦大学生命科学学院,上海200433

出　　处：《微生物与感染》2015年第4期221-227,共7页Journal of Microbes and Infections

基　　金：中国科学院重点部署项目(KSZD-EW-Z-006);上海市科委科技支撑项目(13431900103)

摘　　要：本研究通过同源建模方法,模拟结核分枝杆菌H37Rv来源的吲哚-3-甘油磷酸合成酶(IGPS)的结构,采用分子对接法,以IGPS结构为基础,从包含60 000种化合物的Maybridge化合物库中筛选出能与IGPS活性中心良好结合的化合物,并用抑菌实验等生物学方法进行验证。结果表明,化合物ATB26能与IGPS很好结合,且能体外有效抑制H37Rv和临床分离的敏感和耐药菌株的生长,其对结核分枝杆菌的体外最低抑菌浓度约为0.1μg/ml。细胞毒性实验表明,ATB26与临床常用抗结核药物异烟肼、乙胺丁醇类似,对THP-1细胞系毒性较小。结果提示,化合物ATB26是一个新型IGPS抑制剂,有望开发成为新型的抗结核药,也可作为新型抗结核药物开发的一个潜在靶点。In this study, the structure of indole-3-glycerol phosphate synthase （IGPS） from Mycobacterium tuberculosis （M. tuberculosis） H37Rv was obtained by homologous modeling. Based on the IGPS structure, virtual screening was carried out to select novel inhibitors from the Maybridge database with about sixty thousand organic compounds. Through biological selection, one compound, named ATB26, was identified as a potential inhibitor of IGPS, which showed potent antimycobacterial activity not only against M. tuberculosis H37Rv, but also clinical isolates of multidrug-resistant M. tuberculosis strains with minimum inhibition concentration （MIC） of 0.1 μg/ml. ATB26 could bound tightly to IGPS in vitro and inhibited activity of IGPS. These results suggest that ATB26 is a novel potent inhibitor of IGPS, a potential target for the development of new anti-tuberculosis drugs.

关 键 词：吲哚-3-甘油磷酸合成酶 结核分枝杆菌 抑制剂 

分 类 号：R914.5[医药卫生—药物化学]