Three-dimensional modeling of cytochrome P450 14 alpha-demethylase (CYP51) and interaction of azole fungicide metconazole with CYP51

We have reported the quantitative structure-activity relationships (QSAR) of metconazole, a triazole fungicide and its related compounds, and proposed the interaction mode between CYP51 and metconazole. To confirm our model, we constructed three-dimensional model of phytopathogen's CYP51 by homology modeling on the basis of the recently reported crystal structure of CYP51 of Mycobacterium tuberculosis (MTCYP51). Plant pathogen's CYP51s exhibit 25-28% amino acid sequence identities with MTCYP51. The residues located within 8 A from fluconazole in the crystallized complex of MTCYP51 were identified. The selected amino acids were replaced with those of CYP51 of Botrytis cinerea (BCCYP51), and a model of interaction between metconazole and BCCYP51 was constructed. The modeled three-dimensional structure corresponded to our putative interaction model proposed with the QSAR analyses.