Assessing the safety of new chemicals, without introducing the need for animal testing, is a task of great importance. The Ames test, a widely used bioassay to assess mutagenicity, can be an expensive, wasteful process with animal-derived reagents. Existing in silico methods for the prediction of Ames test results are traditionally based on chemical category formation and can lead to false positive predictions. Category formation also neglects the intrinsic chemistry associated with DNA reactivity. Activation energies and HOMO/LUMO energies for thirty 1,4 Michael acceptors were calculated using a model nucleobase and were further used to predict the Ames test result of these compounds. The proposed model builds upon existing work and examines the fundamental toxicant-target interactions using density functional theory transition-state modeling. The results show that Michael acceptors with activation energies <20.7 kcal/mol and LUMO energies < -1.85 eV are likely to act as direct mutagens upon exposure to DNA.

译文

在不需要进行动物测试的情况下评估新化学品的安全性是一项非常重要的任务。Ames测试是一种广泛用于评估诱变性的生物测定法,使用动物衍生试剂可能是一个昂贵,浪费的过程。现有的用于预测Ames测试结果的计算机方法传统上是基于化学类别的形成,并且可能导致假阳性预测。类别形成也忽略了与DNA反应性相关的内在化学。使用模型核碱基计算三十个1,4 Michael受体的活化能和HOMO/LUMO能量,并进一步用于预测这些化合物的Ames测试结果。所提出的模型建立在现有工作的基础上,并使用密度泛函理论过渡态模型研究了基本的毒物-目标相互作用。结果表明,活化能 <20.7 kcal/mol和LUMO能量 <-1.85 eV的Michael受体在暴露于DNA时可能充当直接诱变剂。

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