A quantitative structure-activity relationship analysis on a series of alkyl benzenes metabolized by human cytochrome...

The results of quantitative structure-activity relationships for eight alkyl benzenes undergoing oxidative metabolism via human CYP2E1 are reported. Molecular orbital calculations via the AM1 method were employed for the generation of electronic structural descriptors against experimentally generated kinetic data for CYP2E1-mediated metabolism. The findings point to the importance of electronic structural properties of the molecules themselves, particularly the role of frontier orbitals, in determining rates of metabolism. Other factors appear to be responsible for the affinity of these substrates for the CYP2E1 enzyme however, such as its lipophilic character. The results are consistent with the interactive molecular modeling of these compounds within the putative active site of human CYP2E1 constructed from the CYP2C5 template, where it was found that pi-pi stacking interactions between aromatic rings are important for the binding of substrates to the CYP2E1 active site, together with contributions from desolvation entropy changes accompanying substrate binding.