Heteroatom-Induced Metabolic Differences: Computational Study on the Mechanism of CYP1A1-Mediated Metabolic Activation of Dibenz[a,j]acridine.

Dibenz[,]acridine (DBA) is a probable human carcinogen classified by the International Agency for Research on Cancer. Its metabolic activation in humans should not be directly extrapolated from that of classical polycyclic aromatic compounds, due to the presence of heteroatoms. This study combined molecular docking, molecular dynamics (MD) simulations, and quantum mechanical (QM) calculations to elucidate the binding modes, interactions, and regioselectivity metabolic mechanisms of DBA within human cytochrome P450 1A1 (CYP1A1). The results show that the nitrogen atom exhibits greater electrophilic reactivity than the ring carbons, but the geometric constraints of the active site force DBA to adopt a side-on mode toward heme, endowing the C2 and C3 sites with more favorable spatial conditions for metabolism. QM calculations further indicate C3 as the dominant metabolic site, with a lower rate-determining step energy barrier (19.37 kcal·mol), and a more stable epoxide product (-13.69 kcal·mol). The metabolic regioselectivity of DBA is governed by a synergy between its intrinsic properties and spatial factors. Moreover, the metabolic differences between DBA and the analogous -dibenzo[,]carbazole originate from the distinct nitrogen characteristics. This study elucidates the metabolic activation of DBA in human CYP1A1 and improves the theoretical framework for heterocyclic aromatic compounds metabolism.