Screening of potential non-azole inhibitors of lanosterol14-alpha demethylase (CYP51) of Candida fungi

Kaluzhskiy L.A.1 , Ershov P.V.1, Yablokov E.O.1, Mezentsev Y.V.1, Gnedenko O.V.1, Shkel T.V.2, Gilep A.A.2, Usanov S.A.2, Ivanov A.S.1

1. Institute of Biomedical Chemistry, Moscow, Russia
2. Institute of Bioorganic Chemistry, Minsk, Belarus
Section: Experimental Study
DOI: 10.18097/PBMC20216701042      PubMed Id: 33645521
Year: 2021  Volume: 67  Issue: 1  Pages: 42-50
Currently, opportunistic fungi of the genus Candida are the main causative agents of mycoses, which are especially severe upon condition of acquired immunodeficiency. The main target for the development of new antimycotics is the cytochrome P450 51 (CYP51) of the pathogenic fungus. Due to the widespread distribution of Candida strains resistancy to inhibitors of the azole class, the screening for CYP51 inhibitors both among non-azole compounds and among clinically used drugs repurposing as antimycotics is becoming urgent. To identify potential inhibitors from the non-azole group, an integrated approach was applied, including bioinformatics analysis, computer molecular modeling, and a surface plasmon resonance (SPR) technology. Using in silico modeling, the binding sites for acetylsalicylic acid, ibuprofen, chlorpromazine and haloperidol (this compounds, according to the literature, showed antimycotic activity) were predicted in the active site of CYP51 of Candida albicans and Candida glabrata. The Kd values of molecular complexes of acetylsalicylic acid, ibuprofen and haloperidol with CYP51, determined by SPR analysis, ranged from 18 μM to 126 μM. It was also shown that structural derivatives of haloperidol, containing various substituents, could be positioned in the active site of CYP51 of Candida albicans with the possible formation of coordination bonds between the hydroxyl groups of the derivatives and the iron atom in the heme of CYP51. Thus, the potential basic structures of non-azole compounds have been proposed, which can be used for the design of new CYP51 inhibitors of Candida fungi.
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Keywords: CYP51 inhibitors, surface plasmon resonance, docking, antimycotic, drugs
Supplementary materials:

Kaluzhskiy, L. A., Ershov, P. V., Yablokov, E. O., Mezentsev, Y. V., Gnedenko, O. V., Shkel, T. V., Gilep, A. A., Usanov, S. A., Ivanov, A. S. (2021). Screening of potential non-azole inhibitors of lanosterol14-alpha demethylase (CYP51) of Candida fungi. Biomeditsinskaya Khimiya, 67(1), 42-50.
This paper is also available as the English translation: 10.1134/S1990750821030045
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