Olsen Lars, Rydberg Patrik, Rod Thomas H, Ryde Ulf
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
J Med Chem. 2006 Nov 2;49(22):6489-99. doi: 10.1021/jm060551l.
We have estimated the activation energy for hydrogen abstraction by compound I in cytochrome P450 for a diverse set of 24 small organic substrates using state-of-the-art density functional theory (B3LYP). We then show that these results can be reproduced by computationally less demanding methods, for example, by using small organic mimics of compound I with both B3LYP and the semiempirical AM1 method (mean absolute error of 3-4 kJ/mol) or by calculating the bond dissociation energy, without relaxation of the radical (B3LYP) or estimated from three-point fit to a Morse potential (AM1; errors of 4 and 5 kJ/mol, respectively). We can assign activation energies of 74, 61, 53, 47, and 30 kJ/mol to primary carbons, secondary/tertiary carbons, carbons with adjacent sp(2) or aromatic groups, ethers/thioethers, and amines, respectively, which gives a very simple and predictive model. Finally, some of the less demanding methods are applied to study the CYP3A4 metabolism of progesterone and dextromethorphan.
我们使用最先进的密度泛函理论（B3LYP），针对24种不同的小分子有机底物，估算了细胞色素P450中化合物I夺取氢原子的活化能。然后我们表明，这些结果可以通过计算要求较低的方法重现，例如，使用化合物I的小分子有机模拟物，结合B3LYP和半经验AM1方法（平均绝对误差为3 - 4 kJ/mol），或者通过计算键解离能，不考虑自由基弛豫（B3LYP）或根据对莫尔斯势的三点拟合估算（AM1；误差分别为4和5 kJ/mol）。我们可以分别将74、61、53、47和30 kJ/mol的活化能赋予伯碳、仲/叔碳、带有相邻sp(2)或芳基的碳、醚/硫醚和胺，这给出了一个非常简单且具有预测性的模型。最后，一些计算要求较低的方法被应用于研究孕酮和右美沙芬的CYP3A4代谢。
