Predicting activation enthalpies of cytochrome-P450-mediated hydrogen abstractions. 2. Comparison of semiempirical PM3, SAM1, and AM1 with a density functional theory method.
Predicting activation enthalpies of cytochrome-P450-mediated hydrogen abstractions. 2. Comparison of semiempirical PM3, SAM1, and AM1 with a density functional theory method.
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预测细胞色素 P450 介导的氢提取的活化焓。
DOI：
10.1021/ci8003946
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发表时间：
2009
影响因子：
5.6
通讯作者：
Reisfeld,Brad
中科院分区：
文献类型：
--
作者：
Mayeno,ArthurN;Robinson,JonathanL;Yang,RaymondSH;Reisfeld,Brad
预测外源物质的生物转化对于化学和制药行业以及毒理学来说非常重要。在这里，我们扩展并评估了 Korzekwa、Jones 和 Gillette (J. Am. Chem. Soc.1990,112, 7042−7046) 的快速方法，以估计细胞色素 P450 (CYP) 酶夺氢的活化焓 (ΔH⧧)，使用对亚硝基苯氧基自由基 (PNPO) 作为 CYP 活性氧的简单替代物。 ΔH⧧ 使用线性回归模型进行估计，使用反应焓和电离能（底物自由基）作为预测变量，通过半经验 (SE) 方法计算。而 Korzekwa 等人。使用SE方法AM1，我们应用PM3和SAM1并比较三种方法的结果。对于 24 种底物，AM1、PM3 和 SAM1 衍生的回归模型显示计算的 ΔH⧧ 与预测的 ΔH⧧ 之间的相关性的 R2 值分别为 0.89、0.90 和 0.93。此外，我们将使用 PNPO 自由基半经验计算的 ΔH⧧ 与 Olsen 等人计算的密度泛函理论 (DFT) B3LYP 活化能进行了比较。 (J. Med. Chem.2006,49, 6489−6499) 使用更真实的铁氧卟啉模型，结果揭示了 PNPO 激进模型的局限性。因此，使用 SE 预测器开发的预测模型可提供快速且总体内部一致的结果，但应谨慎解释和使用它们。
Predicting the biotransformation of xenobiotics is important in the chemical and pharmaceutical industries, as well as in toxicology. Here, we extend and evaluate the rapid methodology of Korzekwa, Jones, and Gillette (J. Am. Chem. Soc.1990,112, 7042−7046) to estimate the activation enthalpy (ΔH⧧) of hydrogen-abstraction by cytochrome P450 (CYP) enzymes, using thep-nitrosophenoxy radical (PNPO) as a simple surrogate for the CYP active oxygen species. The ΔH⧧is estimated with a linear regression model using the reaction enthalpy and ionization energy (of the substrate radical) as predictor variables, calculated by semiempirical (SE) methods. While Korzekwa et al. used the SE method AM1, we applied PM3 and SAM1 and compared the results of the three methods. For 24 substrates, the AM1-, PM3-, and SAM1-derived regression models showedR2values of 0.89, 0.90, and 0.93, respectively, for the correlation between calculated and predicted ΔH⧧. Furthermore, we compared the ΔH⧧calculated semiempirically using PNPO radical with density functional theory (DFT) B3LYP activation energies calculated by Olsen et al. (J. Med. Chem.2006,49, 6489−6499) using a more realistic iron−oxo−porphine model, and the results revealed limitations of the PNPO radical model. Thus, predictive models developed using SE predictors provide rapid and generally internally consistent results, but they should be interpreted and used cautiously.