A systems biology approach to identify effective cocktail drugs.
A systems biology approach to identify effective cocktail drugs.
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DOI：
10.1186/1752-0509-4-s2-s7
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发表时间：
2010-09-13
影响因子：
--
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Wu Z;Zhao XM;Chen L
复杂的疾病，如2型糖尿病，通常是由多种因素引起的，这阻碍了有效药物的发现。为了对抗这些疾病，联合治疗方案或联合药物提供了另一种方法，并正在成为治疗复杂疾病的标准方法。然而，现有的联合药物大多是基于临床经验或试验-试验策略开发的，不仅耗时而且费用昂贵。在本文中，我们提出了一种新的基于网络的系统生物学方法，通过利用高通量数据来识别有效的药物组合。我们假设在给药后，网络细胞系统中的一个子网络或通路将受到影响。因此，受影响的子网可以用来评估药物的整体效果，通过比较受单个药物影响的子网与受联合药物影响的子网，从而帮助确定有效的药物组合。在这项工作中，我们首先通过整合蛋白质相互作用、蛋白质- dna相互作用和信号通路构建了一个分子相互作用网络。然后开发了一种新模型来检测受毒品影响的子网。此外，我们提出了一个新的评分来评估一种药物的整体效果，同时考虑到疗效和副作用。作为一项试点研究，我们应用所提出的方法来确定用于治疗2型糖尿病的有效药物组合。我们的方法检测了二甲双胍和罗格列酮的组合，罗格列酮实际上是Avandamet，一种成功用于治疗2型糖尿病的药物。实际生物学数据的实验结果证明了该方法的有效性和高效性，不仅可以准确地检测出有效的药物鸡尾酒组合，而且大大减少了昂贵和繁琐的试错实验。
Complex diseases, such as Type 2 Diabetes, are generally caused by multiple factors, which hamper effective drug discovery. To combat these diseases, combination regimens or combination drugs provide an alternative way, and are becoming the standard of treatment for complex diseases. However, most of existing combination drugs are developed based on clinical experience or test-and-trial strategy, which are not only time consuming but also expensive. In this paper, we presented a novel network-based systems biology approach to identify effective drug combinations by exploiting high throughput data. We assumed that a subnetwork or pathway will be affected in the networked cellular system after a drug is administrated. Therefore, the affected subnetwork can be used to assess the drug's overall effect, and thereby help to identify effective drug combinations by comparing the subnetworks affected by individual drugs with that by the combination drug. In this work, we first constructed a molecular interaction network by integrating protein interactions, protein-DNA interactions, and signaling pathways. A new model was then developed to detect subnetworks affected by drugs. Furthermore, we proposed a new score to evaluate the overall effect of one drug by taking into account both efficacy and side-effects. As a pilot study we applied the proposed method to identify effective combinations of drugs used to treat Type 2 Diabetes. Our method detected the combination of Metformin and Rosiglitazone, which is actually Avandamet, a drug that has been successfully used to treat Type 2 Diabetes. The results on real biological data demonstrate the effectiveness and efficiency of the proposed method, which can not only detect effective cocktail combination of drugs in an accurate manner but also significantly reduce expensive and tedious trial-and-error experiments.