Quantitative Structure–Activity Relationship for Inhibition of CYP2B6 and CYP3A4 by Azole Compounds – Comparison with Their Binding Affinity

Abstract Azole compounds are widely used as antifungal agents. They interact with cytochrome P450 14DM (CYP51) via coordination of the nucleophilic nitrogen of their heterocyclic ring to the heme iron in CYP51. In our previous study, we showed that the binding affinity of eighteen azole compounds for rat CYP2B and CYP3A was nicely expressed by the bilinear model of log P. In this study, the same azole compounds were examined as to their inhibitory effect on the substrates for human CYP2B6 and CYP3A4. The inhibitory activity determined was analyzed as to the molecular properties of the azole compounds. A nice correlation was found with the bilinear model of log P. These results suggested that the molecular hydrophobicity of the azole compounds plays a major role in the inhibition as well as in the binding. For the binding, HOMO was significant as an additional descriptor in the correlation equations, whereas the existence of a hydroxyl group was significant for the inhibition.