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Antimicrobial Agents and Chemotherapy, February 2004, p. 568-574, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.568-574.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Three-Dimensional Models of Wild-Type and Mutated Forms of Cytochrome P450 14{alpha}-Sterol Demethylases from Aspergillus fumigatus and Candida albicans Provide Insights into Posaconazole Binding

Li Xiao,1* Vincent Madison,1 Andrew S. Chau,2 David Loebenberg,2 Robert E. Palermo,2 and Paul M. McNicholas2

Departments of Structural Chemistry,1 Antimicrobial Therapy and Molecular Genetics, Schering-Plough Research Institute, Kenilworth, New Jersey 070332

Received 27 August 2003/ Returned for modification 3 October 2003/ Accepted 24 October 2003

The cytochrome P450 sterol 14{alpha}-demethylase enzyme (CYP51) is the target of azole antifungals. Azoles block ergosterol synthesis, and thereby fungal growth, by binding in the active-site cavity of the enzyme and ligating the iron atom of the heme cofactor through a nitrogen atom of the azole. Mutations in and around the CYP51 active site have resulted in azole resistance. In this work, homology models of the CYP51 enzymes from Aspergillus fumigatus and Candida albicans were constructed based on the X-ray crystal structure of CYP51 from Mycobacterium tuberculosis. Using these models, binding modes for voriconazole (VOR), fluconazole (FLZ), itraconazole (ITZ), and posaconazole (POS) were predicted from docking calculations. Previous work had demonstrated that mutations in the vicinity of the heme cofactor had a greater impact on the binding of FLZ and VOR than on the binding of POS and ITZ. Our modeling data suggest that the long side chains of POS and ITZ occupy a specific channel within CYP51 and that this additional interaction, which is not available to VOR and FLZ, serves to stabilize the binding of these azoles to the mutated CYP51 proteins. The model also predicts that mutations that were previously shown to specifically impact POS susceptibility in A. fumigatus and C. albicans act by interfering with the binding of the long side chain.

* Corresponding author. Mailing address: Schering-Plough Research Institute, 2015 Galloping Hill Rd., K15-L0300, Kenilworth, NJ 07033. Phone: (908) 740-3845. Fax: (908) 740-4640. E-mail: li.xiao{at}spcorp.com.

Antimicrobial Agents and Chemotherapy, February 2004, p. 568-574, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.568-574.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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