How Frequently Are Pan-Assay Interference Compounds Active? Large-Scale Analysis of Screening Data Reveals Diverse Activity Profiles, Low Global Hit Frequency, and Many Consistently Inactive Compounds
How Frequently Are Pan-Assay Interference Compounds Active? Large-Scale Analysis of Screening Data Reveals Diverse Activity Profiles, Low Global Hit Frequency, and Many Consistently Inactive Compounds
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DOI：
10.1021/acs.jmedchem.7b00154
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发表时间：
2017-05-11
影响因子：
7.3
通讯作者：
Bajorath, Juergen
中科院分区：
文献类型：
--
作者：
Jasial, Swarit;Hu, Ye;Bajorath, Juergen
未检测到的泛分析干扰化合物（PAINS）在分析中具有假阳性活性，通常通过药物化学程序传播并损害其结果。虽然通常根据个别研究或化学经验对大量的痛经进行了分类，但迄今为止对其活动概况进行系统评估的工作很少。在这里，我们报告了一个大规模的分析行为的疼痛在生物筛选试验。检测到超过23000种经过广泛测试的含有PAINS亚结构的化合物，并确定了它们的命中率。鉴定出许多一贯无活性的化合物。总的来说，命中频率很低，在数百次分析中，pain测试的中位数为2到5次。只有有限的疼痛亚群产生了大量的命中。在一贯不活跃和经常活跃的化合物中经常发现相同的苦痛亚结构，这表明苦痛发生的结构环境调节了它们的作用。
Undetected pan-assay interference compounds (PAINS) with false-positive activities in assays often propagate through medicinal chemistry programs and compromise their outcomes. Although a large number of PAINS have been classified, often on the basis of individual studies or chemical experience, little has been done so far to systematically assess their activity profiles. Herein we report a large-scale analysis of the behavior of PAINS in biological screening assays. More than 23 000 extensively tested compounds containing PAINS substructures were detected, and their hit rates were determined. Many consistently inactive compounds were identified. The hit frequency was low overall, with median values of two to five hits for PAINS tested in hundreds of assays. Only confined subsets of PAINS produced abundant hits. The same PAINS substructure was often found in consistently inactive and frequently active compounds, indicating that the structural context in which PAINS occur modulates their effects.