THEORETICAL MODELS FOR CYTOCHROME P450 MEDIATED OXIDATIONS

无处不在的超家族酶，细胞色素P450， 仍然是许多不同研究努力的重点。 对这些含有单加氧酶的血红素的兴趣源于它们的 催化氧化多种亲脂性物质的能力 内源性(即类固醇、前列腺素和脂肪酸)和 外源性(药物和环境污染物)化合物。 由于它们在药物代谢和毒性方面的重要性， 细胞色素P450氧化的预测模型可能非常 很有用。我们之前曾使用分子建模技术来 细胞色素P450氢提取预测模型的建立 反应。用对亚硝基苯氧基作为反应模型 P450活性氧合物种，观察到线性相关 和修正的Swain-Lupton共振参数的组合 或形成的自由基的电离势。后者 关系给出了预测的估计标准差 0.8千卡/摩尔，这表明有可能获得一个 任何碳氢键的相对能力的估计 通过计算P450介导的氢原子抽象化 产物的相对稳定性和电离势 激进的。我们现在也在测试这个模型 将其扩展到包括芳香族和烯烃氧化。在……里面 用于54羟基化的加成、反应物和产物 对减饱和反应进行建模，并用来预测 每个反应发生的相对倾向。最后，给出了一个模型 开发了芳香酶催化合成雌激素的方法。

The ubiquitous superfamily of enzymes, the cytochrome P450s, continue to be the focus of many diverse research efforts. Interest in these heme containing monooxygenases stem from their ability to catalyze the oxidation of a wide variety of lipophilic endogenous (i.e., steroids, prostaglandins and fatty acids) and exogenous (drugs and environmental contaminants) compounds. Because of their importance in drug metabolism and toxicity, predictive models for cytochrome P450 oxidations could be extremely useful. We have previously used molecular modeling techniques to develop a predictive model for cytochrome P450 hydrogen abstraction reactions. Using the p-nitrosophenoxy radical as a model for the P450 active oxygenating species, a linear correlation was observed and a combination of the modified Swain-Lupton resonance parameter or the ionization potential of the radical formed. The latter relationship gave an estimated standard deviation of the predicted 0.8 kcal/mol, suggesting that it may be possible to obtain an estimate of the relative ability for any carbon-hydrogen bond to undergo P450 mediated hydrogen atom abstraction by calculating the relative stability and ionization potential of the resulting radical. We are now in the process of testing this model as well as expanding it to include aromatic and olefinic oxidations. In addition, reactants and products for 54 hydroxylation and desaturation reactions were modeled and used to predict the relative tendency for each reaction to occur. Finally, a model for the aromatase catalyzed formation of estrogen has been developed.