Performance of Dark Chemical Matter in High Throughput Screening
Performance of Dark Chemical Matter in High Throughput Screening
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DOI：
10.1021/acs.jmedchem.6b01038
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发表时间：
2016-11-10
影响因子：
7.3
通讯作者：
Mukherjee, Prasenjit
中科院分区：
文献类型：
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作者：
Muegge, Ingo;Mukherjee, Prasenjit
对203个高通量筛选进行了统计分析，研究了勃林格殷格翰筛选板中的小分子在之前在越来越多的筛选试验中检测为无活性后显示生物活性的倾向。已在50次或更多次测定中测试并发现无活性的暗化学物质（DCM）化合物表现出与在少得多的测定中测试的化合物相当的命中率。只有在125次或更多次试验中测试为无活性的化合物开始显示出与在少于25次试验中测试的化合物相比高达40%的命中率恶化。发现BI筛选板中观察到的大量DCM化合物与基于概率分析计算的DCM预期分数一致。分析表明，不仅DCM化合物有机会偶尔提供与较高选择性相关的有价值的命中，如Novartis最近所示（Nat.Chem.Biol.2015，11，958），而且几乎没有令人信服的理由将DCM化合物从筛选板中排除，而支持先前未测试或测试较少的化合物。
A statistical analysis of 203 high-throughput screens was conducted studying the propensity of small molecules in the Boehringer Ingelheim screening deck to show biological activity after having tested as inactive previously in a growing number of screening assays. Dark chemical matter (DCM) compounds, which have been tested and found to be inactive in 50 or more assays, exhibit hit rates that are comparable to those of compounds tested in much fewer assays. Only compounds tested as inactive in 125 or more assays started showing a hit rate deterioration of up to 40% compared to compounds tested in less than 25 assays. The observed large number of DCM compounds in the BI screening deck is found to be in line with the expected fraction of DCM calculated based on a probability analysis. The analysis suggests not only that DCM compounds have the chance to occasionally provide valuable hits associated with higher selectivity as recently shown by Novartis (Nat. Chem. Biol. 2015, 11, 958) but that there is little compelling reason to exclude DCM compounds from screening decks in favor of previously untested or less tested compounds.