Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis.
Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis.
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DOI：
10.1371/journal.pcbi.1000423
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发表时间：
2009-07
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;Liu N;Buchmeier N;Tonge PJ;Xie L;Bourne PE
世界各地，包括在工业化国家，耐多药结核病和广泛耐药结核病的增加对人类健康构成巨大威胁，因此需要开发新的、有效的和廉价的抗结核药物。以前，我们开发了一种化学系统生物学方法来识别蛋白质组范围内主要药物的脱靶。在本文中，我们通过发现现有的用于治疗帕金森病的市售药物具有治疗耐多药和广泛耐药结核病的潜力，进一步证明了这种方法的价值。这些药物，恩他卡酮和托尔卡酮，预计会与InhA酶结合并直接抑制底物结合。用康坦片（其有效成分为恩他卡酮）进行体外和体内动力学分析，验证了预测结果。恩他卡酮对结核分枝杆菌的最小抑制浓度（MIC99）约为260.0µM，远低于使用人神经母细胞瘤细胞系的体外细胞毒性模型确定的毒性浓度。此外，动力学分析表明，在恩他卡彭浓度约为80µM时，Comtan抑制InhA活性47.0%。因此，康坦中的活性成分代表了一个有希望的先导化合物，用于开发一类具有良好安全性的新型抗结核治疗药物。更一般地说，本文中描述的协议可以包含在药物发现管道中，以努力发现具有所需安全性的新药物线索，从而加速新药的开发。在世界各地，包括在工业化国家，耐多药结核病和广泛耐药结核病的增加对人类健康构成了巨大威胁。这种耐药性突出表明需要开发新的、有效的和廉价的抗结核药物。不幸的是，传统方法在抗感染药物发现领域取得的成功非常少。设计出既有效又安全的药物是一项挑战。这些挑战反映在将新药推向市场所涉及的高成本上。据估计，成功推出一种新药的费用超过8亿美元。我们开发了一种新的计算策略来系统地识别不同药物靶标家族之间的交叉反应性。在本文中，我们通过发现现有的用于治疗帕金森病的市售药物具有治疗耐多药和广泛耐药结核病的潜力，证明了这种方法的优势。本文所述的方案可以包括在药物发现管道中，以努力加速开发具有较少副作用的新药。
The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. The minimal inhibition concentration (MIC99) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 µM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80 µM. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles. More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development of new drugs. The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health. This resistance highlights the need to develop new, effective and inexpensive anti-tubercular agents. Unfortunately, conventional approaches have yielded very few successes in the field of anti-infective drug discovery. It is a challenge to design drugs with both efficacy and safety. These challenges are reflected in the high costs involved in bringing new drugs to market. It has been estimated that the cost to launch a successful new drug is in excess of US$800 million. We have developed a novel computational strategy to systematically identify cross-reactivity between different drug target families. In this paper we demonstrate the strength of this approach through the discovery that existing commercially available drugs prescribed for the treatment of Parkinson's disease have the potential to treat MDR and XDR tuberculosis. The protocol described herein can be included in a drug discovery pipeline in an effort to accelerate the development of new drugs with reduced side effects.
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影响因子：
7.3
作者：
Miller, WH;Seefeld, MA;Huffman, WF
通讯作者：
Huffman, WF
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4
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影响因子：
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作者：
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通讯作者：
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