A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals

A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID methods was applied as a tool to study and predict the mechanism of action of 100 carcinogenic benzene derivatives. Two 3D-QSAR models were obtained: (i) model of mouse carcinogenicity on the basis of 100 chemicals (model 1) and (ii) model of the differences in mouse and rat carcinogenicity on the basis of 73 compounds (model 2). 3D-QSAR regression maps indicated the important differences in species carcinogenicity, and the molecular positions associated with them. In order to evaluate the role of P450 metabolic process in carcinogenicity, the following approaches were used. The 3D models of CYP2E1 for mouse and rat were built up. A docking study was applied and the important ligand–protein residues interactions and oxidation positions of the molecules were identified. A new approach for quantitative assessment of metabolism pathways was developed, which enabled us to describe the species differences in CYP2E1 metabolism, and how it can be related to differences in the carcinogenic potential for a subset of compounds. The binding energies of the important substituents (local-binding energy—LBE) were calculated, in order to quantitatively demonstrate the contribution of the substituents in metabolic processes. Furthermore, a computational procedure was used for determining energetically favourable binding sites (GRID examination) of the enzymes. The GRID procedure allowed the identification of some important differences, related to species metabolism in CYP2E1. Comparing GRID, 3D-QSAR maps and LBE results, a similarity was identified, indicating a relationship between P450 metabolic processes and the differences in the carcinogenicity.