Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
ACS Chem Biol. 2011 Jan 21;6(1):86-94. doi: 10.1021/cb1002976. Epub 2010 Nov 18.
Small molecules are important not only as therapeutics to treat disease but also as chemical tools to probe complex biological processes. The discovery of novel bioactive small molecules has largely been catalyzed by screening diverse chemical libraries for alterations in specific activities in pure proteins assays or in generating cell-based phenotypes. New approaches are needed to close the vast gap between the ability to study either single proteins or whole cellular processes. This Review focuses on the growing number of studies aimed at understanding in more detail how small molecules perturb particular signaling pathways and larger networks to yield distinct cellular phenotypes. This type of pathway-level analysis and phenotypic profiling provides valuable insight into mechanistic action of small molecules and can reveal off-target effects and improve our understanding of how proteins within a pathway regulate signaling.
小分子不仅作为治疗疾病的药物很重要，而且作为化学工具也可用于探测复杂的生物过程。新型生物活性小分子的发现主要是通过筛选各种化学文库，以在纯蛋白测定中或在产生基于细胞的表型中观察到特定活性的变化来实现的。需要新的方法来缩小研究单个蛋白质或整个细胞过程的能力之间的巨大差距。这篇综述重点介绍了越来越多的旨在更详细地了解小分子如何干扰特定信号通路和更大网络以产生不同细胞表型的研究。这种通路水平的分析和表型分析为小分子的作用机制提供了有价值的见解，并可以揭示非靶向效应，提高我们对通路中蛋白质如何调节信号的理解。
