The incidence of fungal infections has increases significantly in the past two decades. The first azoles generation of antifungal inhibitors of CYP51, have revolutionized treatment of some serious fungal infections. Triazoles has been the leading agents for the control of fungal diseases of humans and animals for over 20 years [1]. According to this an azole derivatives are currently the most widely studied class of antifungal agents. The UR-9825 exhibit two important types of activity against certain fungal pathogens i.e. activity against yeast and filamentous fungi. Up to date the name of compound UR-9825 is Albaconazole and it is undergoing the Phase II clinical trials [2].

Our recent QSAR study for an azole series shown that the biological activity against pathogenic yeast and some filamentous fungi increases with a decreases of the log P and increase polarizability of the agent [3]. These parameters play an important role not only in the penetration and distribution phenomena but also in the interactions of the compound with receptor.

A knowledge-based strategy was used to perform docking experiments of fluconazole and UR-9825 into the catalytic site of the CYP51. The model was constructed on the basis of the sequence homology relationship with the crystal structure of the CYP51 of Mycobacterium tuberculosis MT-CYP51 (pdb code: 1ea1) as template [4].

Albaconazole molecule bind to the catalytic site of CA-CYP51 adopting the similar bio-active conformation as observed in fluconazole crystallized complex with the enzyme.

This study was supported by the UMK research grant no. 13/2008.

REFERENCES

[1]. Chakrabarti, A. Microbiology 2005, 51, 16.

[2]. Aperis, G.; Mylonakis, E. Exp. Opin. Inv. Drugs 2006, 15, 579.

[3]. Nowaczyk, A.; Modzelewska-Banachiewicz, B. in press.

[4]. Podust, L. M.; Poulos, T. L.; Waterman, M. R. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 3068.

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