Stereoselective interaction of an azole antifungal agent with its target, lanosterol 14 alpha-demethylase (cytochrome P-45014DM): a model study with stereoisomers of triadimenol and purified cytochrome P-45014DM from yeast

The effect of the four triadimenol stereoisomers on the purified yeast lanosterol 14 alpha-demethylase (cytochrome P-45014DM), the primary target of azole antifungal agents, was studied. (1S,2R)-Triadimenol was the most potent demethylase inhibitor and bound quantitatively to the enzyme below 0.05 microM. This isomer also interfered with the chemical reduction of cytochrome P-45014DM and the binding of CO to the cytochrome. The other isomers showed a lower inhibitory effect on the enzyme, and the order of activity was (1R,2R) greater than (1R,2S) greater than or equal to (1S,2S). Based on these findings and the reported preferred conformations for the triadimenol stereoisomers (Anderson, N.H. et al., Pestic. Sci. 15:310-316, 1984), it is predicted that orientation of the hydrophobic tert-butyl and p-chlorophenyl groups relative to the azole nitrogen is important to fit the antifungal agent in the active site of the demethylase.