Screening of Potential Non-Azole Inhibitors of Lanosterol 14-Alpha Demethylase (CYP51) of the Candida Fungi

Opportunistic fungi of the genus Candida are currently considered as the major causative agents of mycoses, which are characterized by an especially severe course under conditions of acquired immunodeficiency. The main target for the development of new antimycotics is the cytochrome P450 51 (CYP51) of the pathogenic fungus. The widespread distribution of Candida strains resistant to the azole class of CYP51 inhibitors point to the clear need for the screening for CYP51 inhibitors both among non-azole compounds and among clinically used drugs, which would be repositioned as antimycotics. In this study an integrated approach including bioinformatics analysis, computer molecular modeling, and a surface plasmon resonance (SPR) technology was employed to identify potential inhibitors from the non-azole group. Using in silico modeling, the binding sites for acetylsalicylic acid, ibuprofen, chlorpromazine and haloperidol (these compounds, according to the literature, showed antimycotic activity) were predicted in the active site of CYP51 from Candida albicans and Candida glabrata. The K-d values of molecular complexes of acetylsalicylic acid, ibuprofen and haloperidol with CYP51, determined by SPR analysis, ranged from 18 mu M to 126 mu M. It was also shown that structural derivatives of haloperidol, containing various substituents, could be positioned in the active site Candida albicans CYP51 with possible formation of coordination bonds between the hydroxyl groups of the derivatives and the heme iron atom of CYP51. Thus, the potential lead structures of non-azole compounds have been proposed; they can be used for the design of new CYP51 inhibitors of Candida fungi.

Automated summary

Opportunistic fungi of the genus Candida are major causative agents of mycoses and the development of new antimycotics targeting the cytochrome P450 51 (CYP51) is crucial due to the widespread resistance to azole CYP51 inhibitors. Through bioinformatics analysis, computer molecular modeling, and SPR technology, potential inhibitors from non-azole compounds were identified, showing promising results for the design of new CYP51 inhibitors against Candida fungi.