Chemical genetics employs diverse small-molecule compounds to elucidate biological processes in a manner analogous to the mutagenesis strategies at the core of classical genetics. Screening small-molecule libraries for compounds that induce a phenotype of interest represents the forward chemical genetic approach, whereas the reverse approach involves small molecules targeting a single protein. Here, we review key differences between the goals for small-molecule screening in industry versus academia, recent developments in high-throughput screening, and publicly available resources of compound collections, screening facilities, and databases. A particularly exciting outcome of a chemical genetic screen is the discovery of a previously unknown role for a protein in a pathway together with compounds that affect the function of that protein. In illustrative cases, such discoveries have led to progress toward therapeutic development and more commonly have increased the size of the small molecule "toolbox" available to the research community for the study of biological processes.

译文

化学遗传学采用多种小分子化合物来阐明生物学过程,其方式类似于经典遗传学的核心诱变策略。在小分子文库中筛选诱导目标表型的化合物代表了正向化学遗传方法,而反向方法则涉及靶向单个蛋白质的小分子。在这里,我们回顾了工业界和学术界对小分子筛选的目标,高通量筛选的最新发展以及化合物集合,筛选设施和数据库的公开可用资源之间的主要区别。化学遗传筛选的一个特别令人兴奋的结果是,发现一种蛋白质在通路中的作用是未知的,而化合物会影响该蛋白质的功能。在说明性情况下,这样的发现导致了治疗发展的进步,并且更普遍地增加了可供研究团体用于生物学过程研究的小分子“工具箱”的大小。

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