Modeling and interactions of Aspergillus fumigatus lanosterol 14-alpha demethylase 'A' with azole antifungals

Bioorg Med Chem. 2004 Jun 1;12(11):2937-50. doi: 10.1016/j.bmc.2004.03.034.


Recent identification of the sterol 14-alpha 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-alpha demethylase (AF-CYP51A), using the crystal structure of Mycobacterium tuberculosis 14-alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Antifungal Agents / chemistry*
  • Antifungal Agents / metabolism*
  • Antifungal Agents / pharmacology
  • Aspergillus fumigatus / enzymology*
  • Azoles / chemistry*
  • Azoles / metabolism*
  • Azoles / pharmacology
  • Binding Sites
  • Computational Biology
  • Cytochrome P-450 Enzyme System / chemistry*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Design
  • Fungal Proteins / chemistry*
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Sequence Alignment


  • Antifungal Agents
  • Azoles
  • Fungal Proteins
  • Ligands
  • Cytochrome P-450 Enzyme System
  • cytochrome P-450 CYP51A, Aspergillus