Docking analysis of a series of cytochrome P-450(14) alpha DM inhibiting azole antifungals.

Binding modes of a series of structurally diverse azole antifungals belonging to triazole and imidazole classes have been studied using molecular modeling techniques. The predictive model was derived from docking experiments. The analysis of the resulting model indicated that the N3 of imidazole and N4 of triazole rings are in coordinate bond forming distances with heme iron. The aromatic ring has been found to interact with Phe87, Tyr96, Val295, Val396 and Ile395 at the hydrophobic site of the cytochrome P-450cam. In addition, the hydrogen bonding interaction between an etherial oxygen of compounds 2, 5, 8, 9 and 12 and Tyr96 OH seem to have a significant role. Solvent accessible surface area calculations suggested that the active site of the cytochrome P-450cam is highly hydrophobic. The results are in consistent with the biological activity of these compounds. The proposed active orientation model of azole antifungals could be useful for the rational design of more potent inhibitors.