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化学进展 2013, Vol. 25 Issue (09): 1501-1516 DOI: 10.7536/PC130716 前一篇   后一篇

• 癌症化学预防专辑 •

发现癌症化学预防分子靶标的策略

Ann M. Bode, 董子钢*   

  1. The Hormel Institute University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA
  • 收稿日期:2013-01-16 出版日期:2013-09-25 发布日期:2013-07-31
  • 通讯作者: 董子钢 E-mail:zgdong@hi.umn.edu
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Strategies for Identifying Molecular Targets for Cancer Chemoprevention

Ann M. Bode, Zigang Dong*   

  1. The Hormel Institute University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA
  • Received:2013-01-16 Online:2013-09-25 Published:2013-07-31

癌症发生是一个多阶段的过程,涉及到调控着各种细胞功能的数以百计的基因和基因产物。当今的主流观点认为,可以利用靶向特定或多个癌基因、信号蛋白或转录因子的小分子抑制剂来预防癌症发生。多种食物成分被认为有望成为这样的抑制剂,其中很多似乎都作用于多种肿瘤相关的细胞信号通路,具有强抗癌活性、低毒性和有限的毒副作用。因此,联合用药或者多靶点药物的策略日益被认可。强有力的现代技术对于加速发现药物尤其是可抑制多条细胞信号通路的化合物是必需的。例如,结合超级计算机技术如虚拟筛选、蛋白结构测定和实验室验证分析来鉴定特定抗癌化合物的多种蛋白靶标。本文重点讨论了PI3-K/PTEN/Akt/mTOR 和Ras-Raf-MEK-MAPK 这两条在癌症发生中有重要作用的信号通路,描述了计算机技术在鉴定这些通路的小分子抑制剂中的应用。最后,本文介绍了几个运用上述组合策略所鉴定验证的可用于化学预防的小分子及其蛋白质靶标。

关键词： 虚拟筛选, 癌症发生, 反向对接, 形状相似性搜索, 超级计算机, 计算机策略

Carcinogenesis is a multistage process involving hundreds of genes and gene products that regulate various cellular functions. The prevailing opinion today is that cancer might be prevented with small molecules that target specific or multiple cancer genes, signaling proteins and transcription factors. Some promising small molecule inhibitors include various dietary factors. Many of these factors appear to act on multiple tumor-associated cellular pathways with potent anticancer activity, low toxicity and limited adverse side effects. Combining agents or using individual agents that target multiple pathways is a strategy that is gaining acceptance. Powerful modern technologies are needed to accelerate the process of drug discovery especially to find compounds that can suppress multiple cellular signaling pathways. Combining supercomputer technologies, such as in silico screening, with protein structure determination and experimental laboratory validation assays to identify multiple protein targets of anticancer compounds is an example of technologies needed. This paper highlights two of the signaling pathways known to play an important role in carcinogenesis and describes the computational strategies used to identify small molecule inhibitors of these pathways. Finally, examples of molecules and their protein targets, which have been identified and validated by these combinational strategies for chemoprevention, are presented.

Key words: in silico screening, carcinogenesis, reverse docking, shape similarity searching, supercomputer, computational strategies

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