Screening for small-molecule modulators of disease-relevant targets and phenotypes is the first step on the way to new drugs. Large compound libraries have been synthesized by academia and, particularly, pharmaceutical companies to meet the need for novel chemical entities that are as diverse as possible. Screening of these compound libraries revealed a portion of small molecules that is inactive in more than 100 different assays and was therefore termed “dark chemical matter” (DCM). Deorphanization of DCM promises to yield very selective compounds as they are expected to have less off-target effects. We employed morphological profiling using the Cell Painting assay to detect bioactive DCM. Within the DCM collection, we identified bioactive compounds and confirmed several modulators of microtubules, DNA synthesis, and pyrimidine biosynthesis. Profiling approaches are, therefore, powerful tools to probe compound collections for bioactivity in an unbiased manner and are particularly suitable for deorphanization of DCM.

中文翻译：

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使用细胞绘画测定照亮暗化学物质

筛选疾病相关靶点和表型的小分子调节剂是开发新药的第一步。学术界，特别是制药公司已经合成了大型化合物库，以满足对尽可能多样化的新型化学实体的需求。对这些化合物库的筛选揭示了部分小分子在 100 多种不同的检测中处于非活性状态，因此被称为“暗化学物质”(DCM)。 DCM 的脱孤儿化有望产生非常有选择性的化合物，因为它们预计具有较少的脱靶效应。我们采用细胞涂色法进行形态学分析来检测生物活性 DCM。在 DCM 系列中，我们鉴定了生物活性化合物并确认了微管、DNA 合成和嘧啶生物合成的几种调节剂。因此，分析方法是以公正的方式探测化合物集合的生物活性的强大工具，并且特别适合 DCM 的去孤儿化。