Modeling and interactions of Aspergillus fumigatus lanosterol 14-α demethylase `A' with azole antifungals ☆

Abstract Recent identification of the sterol 14-α demethylase genes (CYP51 A and B) from Aspergillus fumigatus and other species by Mellado et al. ( J. Clin. Microbiol. 2001 , 39 (7), 2431–2438), has opened up possibilities of investigating the interactions of azole antifungals with the enzyme(s) from fungi. This study describes for the first time, a model of the three-dimensional structure of A. fumigatus 14-α demethylase (AF-CYP51A), using the crystal structure of Mycobacterium tuberculosis 14-α demethylase (PDB code:1EA1) as a template. The paper also describes the various interactions between azole antifungals and the target from A. fumigatus (AF-CYP51A). Quantitative evaluation of these interactions is done using COMBINE analysis to understand contributions of active site residues to ligand activity. It also provides explanation for the activity/inactivity of different ligands for AF-CYP51A.