Toward performance-diverse small-molecule libraries for cell-based phenotypic screening using multiplexed high-dimensional profiling
Toward performance-diverse small-molecule libraries for cell-based phenotypic screening using multiplexed high-dimensional profiling
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DOI：
10.1073/pnas.1410933111
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发表时间：
2014-07-29
影响因子：
11.1
通讯作者：
Clemons, Paul A.
中科院分区：
文献类型：
--
作者：
Wawer, Mathias J.;Li, Kejie;Clemons, Paul A.
高通量筛选已成为小分子探针和早期药物发现的支柱。如何建立和发展有效的筛选收集系统的细胞为基础的和生化筛选的问题仍然没有解决。通常认为，化学结构的多样性导致文库的不同生物学性能。在这里，我们证实了早期的结果表明，这种推断并不总是有效的，而是建议使用生物测量的多样性，来自多重分析在构建文库与不同的测定性能模式，基于细胞的屏幕。而不是使用来自数十或数百个完整的测定的结果，这是资源密集型的并且不容易扩展，我们使用基于高维图像的细胞形态和基因表达谱。我们使用超过30，000种化合物对这种方法进行了试点。我们表明，小分子谱可用于选择具有高活性和不同生物性能的化合物集。
High-throughput screening has become a mainstay of small-molecule probe and early drug discovery. The question of how to build and evolve efficient screening collections systematically for cell-based and biochemical screening is still unresolved. It is often assumed that chemical structure diversity leads to diverse biological performance of a library. Here, we confirm earlier results showing that this inference is not always valid and suggest instead using biological measurement diversity derived from multiplexed profiling in the construction of libraries with diverse assay performance patterns for cell-based screens. Rather than using results from tens or hundreds of completed assays, which is resource intensive and not easily extensible, we use high-dimensional image-based cell morphology and gene expression profiles. We piloted this approach using over 30,000 compounds. We show that small-molecule profiling can be used to select compound sets with high rates of activity and diverse biological performance.