Study of species-specific carcinogenicity of benzene derivatives. 2. Combination of Docking and Local Binding Energy (LBE) analysis

A combination of Docking and Local Binding Energy (LBE) methods was applied as a tool to study the differences in carcinogenicity and mechanism of action of 12 benzene derivatives. The role of CYP2E1 metabolic process in the carcinogenicity differences was evaluated. The important ligand-protein interactions and the oxidation positions of the compounds were identified. In particular, the conformational changes in Phe298 explain important differences in mouse and rat CYP2E1 metabolism. The differences in the metabolic pathways were quantitatively assessed by LBE approach, which enabled the establishment of relationship of the former to the differences in the carcinogenicity. The combination of Docking and LBE methods is a helpful conceptual instrument for improving the predictive capacity of the models providing mechanistic details, identifying enzyme roles and the design of more selective chemoprotective agents.