Quantitative Comparison of Enrichment from DNA-Encoded Chemical Library Selections
Quantitative Comparison of Enrichment from DNA-Encoded Chemical Library Selections
复制标题
DOI：
10.1021/acscombsci.8b00116
复制
发表时间：
2019-02-01
影响因子：
--
通讯作者：
Matzuk, Martin M.
中科院分区：
文献类型：
--
作者：
Faver, John C.;Riehle, Kevin;Matzuk, Martin M.
DNA编码的化学文库（DELs）提供了一种高通量和成本效益的途径，用于筛选数十亿个独特的分子，用于对不同的蛋白质靶标进行结合亲和力。从这些文库中鉴定候选化合物涉及亲和选择、DNA测序和测量DNA条形码样品池中的富集。有效结合物的成功检测受许多因素影响，包括选择参数、化学产率、文库扩增、测序深度、测序误差、文库大小和所选富集度量。到目前为止，还没有一个明确的共识，如何从DEL选择富集应衡量或报告。我们提出了一个标准化的z分数富集度量使用二项分布模型，满足重要的标准，是相关的DEL选择数据的分析。引入的度量是强大的文库多样性和采样方面，并允许从平行DEL选择富集的n-cadrons的定量比较。这些特征使得比较富集分析策略成为可能，其可以在早期药物发现中提供关于命中化合物的有价值的信息。
DNA-encoded chemical libraries (DELs) provide a high-throughput and cost-effective route for screening billions of unique molecules for binding affinity for diverse protein targets. Identifying candidate compounds from these libraries involves affinity selection, DNA sequencing, and measuring enrichment in a sample pool of DNA barcodes. Successful detection of potent binders is affected by many factors, including selection parameters, chemical yields, library amplification, sequencing depth, sequencing errors, library sizes, and the chosen enrichment metric. To date, there has not been a clear consensus about how enrichment from DEL selections should be measured or reported. We propose a normalized z-score enrichment metric using a binomial distribution model that satisfies important criteria that are relevant for analysis of DEL selection data. The introduced metric is robust with respect to library diversity and sampling and allows for quantitative comparisons of enrichment of n-synthons from parallel DEL selections. These features enable a comparative enrichment analysis strategy that can provide valuable information about hit compounds in early stage drug discovery.