Anti-cancer Drug Development: Computational Strategies to Identify and Target Proteins Involved in Cancer Metabolism
Anti-cancer Drug Development: Computational Strategies to Identify and Target Proteins Involved in Cancer Metabolism
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DOI：
10.2174/138161213804581855
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发表时间：
2013-02-01
影响因子：
3.1
通讯作者：
Kirchmair, Johannes
中科院分区：
文献类型：
--
作者：
Mak, Lora;Liggi, Sonia;Kirchmair, Johannes
尽管为开发有效的化疗药物做出了大量努力并且化疗方案取得了重大进展，但癌症仍然是公共卫生的基本负担。抗癌药物设计的主要挑战是高特异性地选择性地靶向癌细胞。通过靶向改变癌细胞代谢来治疗恶性肿瘤的研究得到了计算方法的支持，该方法可以在确定抗癌治疗的候选靶点方面发挥主导作用，并协助发现和优化抗癌药物。天然产物似乎具有抗癌药物开发的特殊结构，而这一特别有价值的化学空间的大部分仍有待探索。在这篇综述中，我们旨在全面概述当前计算机引导抗癌药物开发的策略。我们首先讨论应用于识别新型抗癌靶点的最先进的生物信息学方法，包括机器学习技术、连接图和生物网络分析。随后对分子建模和化学信息学技术进行了广泛的调查，用于开发针对参与癌细胞糖酵解、脂质、NAD(+)、线粒体（TCA 循环）、氨基酸和核酸代谢的蛋白质的药物。专门的部分重点介绍了从天然产物中开发抗癌疗法的最有前途的策略以及新陈代谢的作用，并对正在研究的许多目标中的一些进行了回顾。本次审查涵盖的所有领域均报告了最近的成功案例。最后，我们简要总结了已确定的最有趣的策略，并对抗癌药物开发的未来方向进行了展望。
Cancer remains a fundamental burden to public health despite substantial efforts aimed at developing effective chemotherapeutics and significant advances in chemotherapeutic regimens. The major challenge in anti-cancer drug design is to selectively target cancer cells with high specificity. Research into treating malignancies by targeting altered metabolism in cancer cells is supported by computational approaches, which can take a leading role in identifying candidate targets for anti-cancer therapy as well as assist in the discovery and optimisation of anti-cancer agents. Natural products appear to have privileged structures for anti-cancer drug development and the bulk of this particularly valuable chemical space still remains to be explored. In this review we aim to provide a comprehensive overview of current strategies for computer-guided anti-cancer drug development. We start with a discussion of state-of-the art bioinformatics methods applied to the identification of novel anti-cancer targets, including machine learning techniques, the Connectivity Map and biological network analysis. This is followed by an extensive survey of molecular modelling and cheminformatics techniques employed to develop agents targeting proteins involved in the glycolytic, lipid, NAD(+), mitochondrial (TCA cycle), amino acid and nucleic acid metabolism of cancer cells. A dedicated section highlights the most promising strategies to develop anti-cancer therapeutics from natural products and the role of metabolism and some of the many targets which are under investigation are reviewed. Recent success stories are reported for all the areas covered in this review. We conclude with a brief summary of the most interesting strategies identified and with an outlook on future directions in anti-cancer drug development.