title: In Silico Prediction of Cytochrome P450-Mediated Biotransformations of Xenobiotics: A Case Study of Epoxidation.
abstract: Predicting the biotransformation of xenobiotics is important in toxicology; however, as more compounds are synthesized than can be investigated experimentally, powerful computational methods are urgently needed to prescreen potentially useful candidates. Cytochrome P450 enzymes (P450s) are the major enzymes involved in xenobiotic metabolism, and many substances are bioactivated by P450s to form active compounds. An example is the conversion of olefinic substrates to epoxides, which are intermediates in the metabolic activation of many known or suspected carcinogens. We have calculated the activation energies for epoxidation by the active species of P450 enzymes (an iron-oxo porphyrin cation radical oxidant, compound I) for a diverse set of 36 olefinic substrates with state-of-the-art density functional theory (DFT) methods. Activation energies can be estimated by the computationally less demanding method of calculating the ionization potentials of the substrates, which provides a useful and simple predictive model based on the reaction mechanism; however, the preclassification of these diverse substrates into weakly polar and strongly polar groups is a prerequisite for the construction of specific predictive models with good predictability for P450 epoxidation. This approach has been supported by both internal and external validations. Furthermore, the relation between the activation energies for the regioselective epoxidation and hydroxylation reactions of P450s and experimental data has been investigated. The results show that the computational method used in this work, single-point energy calculations with the B3LYP functional including zero-point energy and solvation and dispersion corrections based on B3LYP-optimized geometries, performs well in reproducing the experimental trends of the epoxidation and hydroxylation reactions.
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ji
authors.affiliation: College of Environmental and Resource Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Liu
mesh_terms: D001711:Biotransformation; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D004852:Epoxy Compounds / Q000737:chemistry*; D015394:Molecular Structure; D014752:Vinyl Chloride / Q000737:chemistry; D015262:Xenobiotics / Q000737:chemistry*
chemical_list: D004852:Epoxy Compounds; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D014752:Vinyl Chloride