The Mycobacterium tuberculosis drugome and its polypharmacological implications.
The Mycobacterium tuberculosis drugome and its polypharmacological implications.
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DOI：
10.1371/journal.pcbi.1000976
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发表时间：
2010-11-04
影响因子：
4.3
通讯作者：
Bourne PE
中科院分区：
文献类型：
--
作者：
Kinnings SL;Xie L;Fung KH;Jackson RM;Xie L;Bourne PE
我们报告了一种计算方法，整合了结构生物信息学，分子建模和系统生物学构建一个药物靶点网络的结构蛋白质组范围内的规模。该方法已应用于结核分枝杆菌（M.tb）的基因组，结核分枝杆菌是当今传播最广泛的传染病之一的病原体。对于所有结构上表征的与推定的结核分枝杆菌受体结合的批准药物，所得到的药物-靶标相互作用网络，我们称为“TB-药物组”。结核病药物组显示，大约三分之一的药物检查有可能被重新定位，以治疗结核病，许多目前尚未开发的结核分枝杆菌受体可能是化学药物，并可能作为新的抗结核病的目标。此外，对结核病药物组的详细分析为围绕药物靶点网络的争议问题提供了新的线索。事实上，我们的研究结果支持了药物靶点网络本质上是模块化的这一观点，进一步说，任何观察到的随机性主要是由有偏见的靶点覆盖引起的。结核病药物组（http：//funsite.sdsc.edu/drugome/TB）有可能成为开发安全有效抗结核药物的宝贵资源。更一般地，该方法可以应用于其他感兴趣的病原体，随着通过结构生物学/基因组学的持续努力确定更多的结构蛋白质组，结果得到改善。耐多药结核病在世界范围内的增加对人类健康构成了巨大威胁，并突出了识别新的抗结核药物的必要性。我们开发了一种计算策略，将结核病的病原体结核分枝杆菌的结构蛋白质组与所有结构特征的批准药物联系起来，从而构建了一个蛋白质组范围的药物靶点网络-TB药物组。结核病药物组有可能成为开发安全有效的抗结核药物的宝贵资源。更一般地，靶点和药物空间的蛋白质组范围和多尺度视图可以促进系统的药物发现过程，其同时考虑疾病机制和靶点的可药用性、化合物的药物相似性和ADMET特性以及个体的遗传倾向。最终，通过更好地理解大规模的药物-受体相互作用，它可能有助于降低药物开发中的高损耗率。
We report a computational approach that integrates structural bioinformatics, molecular modelling and systems biology to construct a drug-target network on a structural proteome-wide scale. The approach has been applied to the genome of Mycobacterium tuberculosis (M.tb), the causative agent of one of today's most widely spread infectious diseases. The resulting drug-target interaction network for all structurally characterized approved drugs bound to putative M.tb receptors, we refer to as the ‘TB-drugome’. The TB-drugome reveals that approximately one-third of the drugs examined have the potential to be repositioned to treat tuberculosis and that many currently unexploited M.tb receptors may be chemically druggable and could serve as novel anti-tubercular targets. Furthermore, a detailed analysis of the TB-drugome has shed new light on the controversial issues surrounding drug-target networks. Indeed, our results support the idea that drug-target networks are inherently modular, and further that any observed randomness is mainly caused by biased target coverage. The TB-drugome (http://funsite.sdsc.edu/drugome/TB) has the potential to be a valuable resource in the development of safe and efficient anti-tubercular drugs. More generally the methodology may be applied to other pathogens of interest with results improving as more of their structural proteomes are determined through the continued efforts of structural biology/genomics. The worldwide increase in multi-drug resistant TB poses a great threat to human health and highlights the need to identify new anti-tubercular agents. We have developed a computational strategy to link the structural proteome of Mycobacterium tuberculosis, the causative agent of tuberculosis, to all structurally characterized approved drugs, and hence construct a proteome-wide drug-target network – the TB-drugome. The TB-drugome has the potential to be a valuable resource in the development of safe and efficient anti-tubercular drugs. More generally, the proteome-wide and multi-scale view of target and drug space may facilitate a systematic drug discovery process, which concurrently takes into account the disease mechanism and druggability of targets, the drug-likeness and ADMET properties of chemical compounds, and the genetic dispositions of individuals. Ultimately it may help to reduce the high attrition rate in drug development through a better understanding of drug-receptor interactions on a large scale.
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影响因子：
14.8
作者：
Becker, Scott A.;Feist, Adam M.;Herrgard, Markus J.
通讯作者：
Herrgard, Markus J.
影响因子：
64.8
作者：
Gamo, Francisco-Javier;Sanz, Laura M.;Garcia-Bustos, Jose F.
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影响因子：
56.9
作者：
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通讯作者：
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结核分枝杆菌通用应激蛋白 Rv2623 通过 ATP 结合调节细菌生长：建立慢性持续感染的必要条件。
影响因子：
6.7
作者：
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通讯作者：
Chan J
影响因子：
46.9
作者：
Cheng, Alan C.;Coleman, Ryan G.;Huang, Enoch S.
通讯作者：
Huang, Enoch S.