Using Transition State Modeling To Predict Mutagenicity for Michael Acceptors
Using Transition State Modeling To Predict Mutagenicity for Michael Acceptors
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DOI：
10.1021/acs.jcim.8b00130
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发表时间：
2018-06-01
影响因子：
5.6
通讯作者：
Russell, Paul J.
中科院分区：
文献类型：
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作者：
Allen, Timothy E. H.;Grayson, Matthew N.;Russell, Paul J.
艾姆斯致突变性测定是一项长期建立的体外测试，用于测量全球监管测试中使用的新化学品的致突变性潜力。 Ames 分析建模的关键计算方法之一依赖于基于不同亲电子化合物的化学类别的形成，这些化合物能够直接与 DNA 反应并形成共价键。这种方法有时会预测误报，因为并非所有迈克尔受体都被发现是艾姆斯阳性。这种共价键的形成可以使用密度泛函理论过渡态模型进行计算探索。我们已将这种方法应用于致突变性，使我们能够计算 α,β-不饱和羰基与 DNA 鸟嘌呤核碱基模型系统反应所需的活化能。这些计算使我们能够确定活化能大于或等于 25.7 kcal/mol 的化合物不能直接与 DNA 结合。这使我们能够降低计算预测的致突变性测定的假阳性率。该方法可用于研究其他能够导致毒理学结果的共价键形成反应，并了解有关实验结果的更多信息。
The Ames mutagenicity assay is a long established in vitro test to measure the mutagenicity potential of a new chemical used in regulatory testing globally. One of the key computational approaches to modelling the Ames assay relies on the formation of chemical categories based on the different electrophilic compounds that are able to react directly with DNA and form a covalent bond. Such approaches sometimes predict false positives, as not all Michael acceptors are found to be Ames positive. The formation of such covalent bonds can be explored computationally using density functional theory transition state modelling. We have applied this approach to mutagenicity, allowing us to calculate the activation energy required for alpha,beta-unsaturated carbonyls to react with a model system for the guanine nucleobase of DNA. These calculations have allowed us to identify that chemical compounds with activation energies greater or equal to 25.7 kcal/mol are not able to bind directly to DNA. This allows us to reduce the false positive rate for computationally predicted mutagenicity assays. This methodology can be used to investigate other covalent bond forming reactions able to lead to toxicological outcomes, and learn more about experimental results.