In Silico simulation of Cytochrome P450-Mediated metabolism of aromatic amines: A case study of N-Hydroxylation

Aromatic amines, the widely used raw materials in industry, cause long-term exposure to human bodies. They can be metabolized by cytochrome P450 enzymes to form active electrophilic compounds, which will potentially react with nucleophilic DNA to exert carcinogenesis. The short lifetime and versatility of the oxidant (a high-valent iron (IV)-oxo species, compound I) of P450 enzymes prompts us to use theoretical methods to investigate the metabolism of aromatic amines. In this work, the density functional theory (DFT) has been employed to simulate the hydroxylation metabolism through H-abstraction and to calculate the activation energy of this reaction for 28 aromatic amines. The results indicate that the steric effects, inductive effects and conjugative effects greatly contribute to the metabolism activity of the chemicals. The further correlation reveals that the dissociation energy of -NH 2 ( BDE N-H ) can successfully predict the time-consuming calculated activation energy ( R 2 for aromatic and heteroaromatic amines are 0.93 and 0.86, respectively), so BDE N-H can be taken as a key parameter to characterize the relative stability of aromatic amines in P450 enzymes and further to quickly assess their potential toxicity. The validation results prove such relationship has good statistical performance ( q cv 2 for aromatic and heteroaromatic amines are 0.95 and 0.90, respectively) and can be used to other aromatic amines in the application domain, greatly reducing computational cost and providing useful support for experimental research. • The N-hydroxylation of 28 aromatic amines mediated by P450s has been simulated. • The activation energies of H-abstraction (Δ Ε ) have been calculated by DFT method. • The steric, inductive and conjugative effects contribute to the metabolism reactivity. • A linear correlation between the bond energy ( BDE N-H ) and Δ Ε has been built. • The models can quickly predict the metabolism activity of aromatic amines.