A Multidimensional Strategy to Detect Polypharmacological Targets in the Absence of Structural and Sequence Homology
A Multidimensional Strategy to Detect Polypharmacological Targets in the Absence of Structural and Sequence Homology
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DOI：
10.1371/journal.pcbi.1000648
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发表时间：
2010-01-01
影响因子：
4.3
通讯作者：
McCammon, J. Andrew
中科院分区：
文献类型：
--
作者：
Durrant, Jacob D.;Amaro, Rommie E.;McCammon, J. Andrew
传统的药物设计秉承“一种基因、一种药物、一种疾病”的理念。以多靶点药物为核心的多元药理学已成为药物发现的新范式。通过多种药理机制作用的药物的合理设计可以生产出具有更高治疗效力的化合物，并且不太可能对其产生耐药性。此外，识别多个蛋白质靶点对于副作用预测也是至关重要的。三分之一的潜在治疗化合物在临床试验中失败或后来因通常由脱靶结合引起的不可接受的副作用而被从市场上移除。在目前的工作中，我们介绍了一种多维策略，用于在与主要目标蛋白没有全局结构和序列同源性的情况下识别已知小分子抑制剂的次要靶点。为了证明该策略的有效性，我们确定了已知的布鲁氏锥虫RNA编辑连接酶1的微摩尔抑制剂4，5-dihydroxy-3-(1-naphthyldiazenyl)-2，7-naphthalenedisulfonic酸的几个靶点。由于它能够识别潜在的二级靶点，这里描述的策略可能在未来减少药物副作用和/或增加多元药理学的努力中发挥有用的作用。
Conventional drug design embraces the "one gene, one drug, one disease" philosophy. Polypharmacology, which focuses on multi-target drugs, has emerged as a new paradigm in drug discovery. The rational design of drugs that act via polypharmacological mechanisms can produce compounds that exhibit increased therapeutic potency and against which resistance is less likely to develop. Additionally, identifying multiple protein targets is also critical for side-effect prediction. One third of potential therapeutic compounds fail in clinical trials or are later removed from the market due to unacceptable side effects often caused by off-target binding. In the current work, we introduce a multidimensional strategy for the identification of secondary targets of known small-molecule inhibitors in the absence of global structural and sequence homology with the primary target protein. To demonstrate the utility of the strategy, we identify several targets of 4,5-dihydroxy-3-(1-naphthyldiazenyl)-2,7-naphthalenedisulfonic acid, a known micromolar inhibitor of Trypanosoma brucei RNA editing ligase 1. As it is capable of identifying potential secondary targets, the strategy described here may play a useful role in future efforts to reduce drug side effects and/or to increase polypharmacology.