Crews Craig M
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
Chem Biol. 2010 Jun 25;17(6):551-5. doi: 10.1016/j.chembiol.2010.05.011.
Biologically active small molecules have long proven useful in the exploration of cell biology. Although many early compounds were by-products of drug development efforts, recent increased small molecule screening efforts in academia have expanded the repertoire of biological processes investigated to include areas of biology that are not of immediate pharmaceutical interest. Many of these new bioassays score for small molecule-induced phenotypic changes at the cellular or even organismal level and thus have been described as "chemical genetic" screens. However, this analogy with traditional genetic screens is misleading; although each gene has roughly an equivalent chance of being mutated in a traditional genetic screen, the amount of "proteomic space" that a chemical genetics approach can reach using current small molecule libraries is considerably smaller. Thus, new chemical biology methodologies are needed to target the remaining "undruggable proteome" with small druglike molecules.
长期以来，生物活性小分子在细胞生物学探索中已被证明是有用的。尽管许多早期化合物是药物开发努力的副产品，但最近学术界小分子筛选工作的增加，扩大了所研究的生物过程的范围，包括那些并非直接具有制药意义的生物学领域。许多这些新的生物测定法在细胞甚至生物体水平上对小分子诱导的表型变化进行评分，因此被描述为“化学遗传学”筛选。然而，这种与传统遗传筛选的类比具有误导性；虽然在传统遗传筛选中每个基因发生突变的机会大致相等，但使用当前小分子文库的化学遗传学方法能够触及的“蛋白质组空间”量要小得多。因此，需要新的化学生物学方法，用类似药物的小分子靶向剩余的“不可成药蛋白质组”。
