Application of a New Scaffold Concept for Computational Target Deconvolution of Chemical Cancer Cell Line Screens.
Application of a New Scaffold Concept for Computational Target Deconvolution of Chemical Cancer Cell Line Screens.
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DOI：
10.1021/acsomega.7b00215
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发表时间：
2017-04-30
期刊：
影响因子：
4.1
通讯作者：
Bajorath J
中科院分区：
文献类型：
--
作者：
Kunimoto R;Dimova D;Bajorath J
表型分析的靶向去卷积是化学生物学和药物开发领域的研究热点。最终目标是确定产生有趣表型读数的化合物的目标。已经设计了各种实验和计算策略来帮助这一过程。一种广泛应用的计算方法根据新的活性分子与具有针对已知目标的活性的化合物的化学相似性来推断其假定的目标。在这里，我们介绍了一种基于分子支架的变体，用于从化学癌细胞系筛选中进行基于相似性的靶点去卷积，作为表型分析的模型系统。将一种新的支架类型用于基于子结构的相似性评价，称为基于模拟序列的(ASB)支架。与传统的支架和基于化合物的相似性计算相比，通过筛选命中和生物活性参考化合物而产生的以ASB支架为中心的靶点分配在有意义的方式上限制了靶点假设的数量，并导致候选对象中已知癌症靶点的显著丰富。
Target deconvolution of phenotypic assays is a hot topic in chemical biology and drug discovery. The ultimate goal is the identification of targets for compounds that produce interesting phenotypic readouts. A variety of experimental and computational strategies have been devised to aid this process. A widely applied computational approach infers putative targets of new active molecules on the basis of their chemical similarity to compounds with activity against known targets. Herein, we introduce a molecular scaffold-based variant for similarity-based target deconvolution from chemical cancer cell line screens that were used as a model system for phenotypic assays. A new scaffold type was used for substructure-based similarity assessment, termed analog series-based (ASB) scaffold. Compared with conventional scaffolds and compound-based similarity calculations, target assignment centered on ASB scaffolds resulting from screening hits and bioactive reference compounds restricted the number of target hypotheses in a meaningful way and lead to a significant enrichment of known cancer targets among candidates.
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