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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries
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Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries

机译：定量高通量筛选：一种基于滴定的方法，可以有效地识别大型化学文库中的生物活性

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High-throughput screening (HITS) of chemical compounds to identify modulators of molecular targets is a mainstay of pharmaceutical development. Increasingly, HITS is being used to identify chemical probes of gene, pathway, and cell functions, with the ultimate goal of comprehensively delineating relationships between chemical structures and biological activities. Achieving this goal will require methodologies that efficiently generate pharmacological data from the primary screen and reliably profile the range of biological activities associated with large chemical libraries. Traditional HTS, which tests compounds at a single concentration, is not suited to this task, because HTS is burdened by frequent false positives and false negatives and requires extensive follow-up testing. We have developed a paradigm, quantitative HITS (qHTS), tested with the enzyme pyruvate kinase, to generate concentration-response curves for > 60,000 compounds in a single experiment. We show that this method is precise, refractory to variations in sample preparation, and identifies compounds with a wide range of activities. Concentration-response curves were classified to rapidly identify pyruvate kinase activators and inhibitors with a variety of potencies and efficacies and elucidate structure-activity relationships directly from the primary screen. Comparison of qHTS with traditional sing le-concentration HTS revealed a high prevalence of false negatives in the single-point screen. This study demonstrates the feasibility of qHTS for accurately profiling every compound in large chemical libraries (> 10(5) compounds). qHTS produces rich data sets that can be immediately mined for reliable biological activities, thereby providing a platform for chemical genomics and accelerating the identification of leads for drug discovery.
机译：化学化合物的高通量筛选（HITS）以识别分子靶标的调节剂是药物开发的主要内容。 HITS越来越多地用于鉴定基因，途径和细胞功能的化学探针，其最终目标是全面描述化学结构与生物活性之间的关系。为了实现这一目标，将需要一种方法，该方法可从主筛查中有效地产生药理学数据，并可靠地描述与大型化学文库相关的生物活性的范围。传统的HTS只能以单一浓度测试化合物，因此不适合此任务，因为HTS经常会出现假阳性和假阴性，并且需要进行大量后续测试。我们已经开发了一种范式，定量HITS（qHTS），并通过丙酮酸激酶进行了测试，可以在单个实验中生成> 60,000种化合物的浓度响应曲线。我们证明了这种方法精确，对样品制备的变化不敏感，并鉴定出具有广泛活性的化合物。对浓度-响应曲线进行分类，以快速识别具有各种效价和功效的丙酮酸激酶激活剂和抑制剂，并直接从初级筛选中阐明结构-活性关系。 qHTS与传统单浓度HTS的比较显示，单点屏幕中假阴性的发生率很高。这项研究证明了qHTS在大型化学文库（> 10（5）个化合物）中准确分析每种化合物的可行性。 qHTS可以生成丰富的数据集，可以立即进行挖掘以进行可靠的生物学活动，从而为化学基因组学提供平台，并加快药物开发线索的识别。

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