Structure-Based Design of DevR Inhibitor Active against Nonreplicating Mycobacterium tuberculosis
Structure-Based Design of DevR Inhibitor Active against Nonreplicating Mycobacterium tuberculosis
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DOI：
10.1021/jm900358q
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发表时间：
2009-10-22
影响因子：
7.3
通讯作者：
Tyagi, Jaya Sivaswami
中科院分区：
文献类型：
--
作者：
Gupta, Rajesh Kumar;Thakur, Tejender S.;Tyagi, Jaya Sivaswami
抗结核治疗针对活跃复制的生物体。迫切需要开发针对结核分枝杆菌持久亚群的药物。 DevR 反应调节剂被认为在缺氧期间的细菌休眠适应中发挥关键作用。我们开发了基于同源性的 DevR 模型，并将其用于抑制剂的合理设计。通过使用具有一些新功能（包括基于水的药效团查询）的方案对 250 万种化合物进行基于计算机药效团的筛选，鉴定出苯基香豆素衍生物（化合物 10）。化合物 10 抑制 DevR 与靶标 DNA 的结合，下调休眠基因转录，并显着降低缺氧但不缺乏营养的休眠细菌或活跃生长的生物体的存活率。我们的研究结果表明，化合物 10 将 DevR“锁定”在非活性构象中，无法结合同源 DNA 并诱导休眠调节子。这些结果为 DevR 作为新靶点提供了概念验证，以开发具有抗结核杆菌活性的分子，
Antitubercular treatment is directed against actively replicating organisms. There is an urgent need to develop drugs targeting persistent subpopulations of Mycobacterium tuberculosis. The DevR response regulator is believed to play a key role in bacterial dormancy adaptation during hypoxia. We developed a homology-based model of DevR and used it for the rational design of inhibitors. A phenylcoumarin derivative (compound 10) identified by in silico pharmacophore-based screening of 2.5 million compounds employing protocols with some novel features including a water-based pharmacophore query, was characterized further. Compound 10 inhibited DevR binding to target DNA, down-regulated dormancy genes transcription, and drastically reduced survival of hypoxic but not nutrient-starved dormant bacteria or actively growing organ ' isms. Our findings suggest that compound 10 "locks" DevR in an inactive conformation that is unable to bind cognate DNA and induce the dormancy regulon. These results provide proof-of-concept for DevR as a novel target to develop molecules with sterilizing activity against tubercle bacilli,