Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space
Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space
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DOI：
10.1021/acscentsci.8b00747
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发表时间：
2018-12-26
影响因子：
18.2
通讯作者：
Rohde, Jason M.
中科院分区：
文献类型：
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作者：
Kearney, Sara E.;Zahoranszky-Kohalmi, Gergely;Rohde, Jason M.
天然产品及其衍生品仍然是新生的治疗潜力的源泉。然而，许多实验室用于生物评估的资源有限，使得它们之前分离或合成的化合物基本上或完全没有测试。为了解决这一问题，与学术和行业研究人员合作，汇集了天然产物的Canvass文库，用于对各种基于细胞和生化的分析进行定量高通量筛选(QHTS)。对文库的物理化学性质、结构多样性以及与公开可用库中化合物的相似性进行的表征表明，Canvass文库包含许多与批准的药物相同的结构元件。使用各种质量控制指标来分析所产生的化验数据，并使用统计方法，例如聚类法和化合物混杂分析来探索所产生的化验曲线。然后根据结构类别和活性分布对单独的化合物进行分类。这里概述了基于这些分类的不同行为以及值得注意的活动。其中一个突出的亮点是(-)-2(S)-卢卡福林的活性，它被发现可以稳定内质网中的钙水平。这里描述的工作流程说明了通过利用自动化和高通量筛选的力量来广泛调查天然产品的生物潜力的试点工作。
Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (-)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.