Stereoselective interaction of an azole antifungal agent with its target, lanosterol 14α‐demethylase (cytochrome p‐45014dm): A model study with stereoisomers of triadimenol and purified cytochrome p‐45014dm from yeast
- 1 January 1990
- Vol. 2 (1) , 10-15
- https://doi.org/10.1002/chir.530020103
Abstract
The effect of the four triadimenol stereoisomers on the purified yeast lanosterol 14α-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 μM. 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) > (1R,2S) ≧ (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.Keywords
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