[Screening of potential non-azole inhibitors of lanosterol14-alpha demethylase (CYP51) of Candida fungi]
- PMID: 33645521
- DOI: 10.18097/PBMC20216701042
[Screening of potential non-azole inhibitors of lanosterol14-alpha demethylase (CYP51) of Candida fungi]
Abstract
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.
V nastoiashchee vremia uslovno-patogennye griby roda Candida iavliaiutsia osnovnymi vozbuditeliami mikozov, kotorye osobenno tiazhelo protekaiut pri nalichii priobretennogo immunodefitsita. Glavnoĭ mishen'iu dlia razrabotki novykh antimikotikov iavliaetsia tsitokhrom R450 51 (CYP51) patogennogo griba. Vsledstvie shirokogo rasprostraneniia rezistentnykh shtammov Candida k ingibitoram iz klassa azolov aktual'nost' priobretaet poisk ingibitorov CYP51 kak sredi soedineniĭ neazol'noĭ prirody, tak i sredi primeniaemykh v klinike lekarstvennykh sredstv, repozitsioniruemykh v kachestve antimikotikov. Dlia identifikatsii potentsial'nykh ingibitorov iz gruppy soedineniĭ neazol'noĭ prirody byl primenen kompleksnyĭ podkhod, vkliuchaiushchiĭ bioinformaticheskiĭ analiz, komp'iuternoe molekuliarnoe modelirovanie i tekhnologiiu poverkhnostnogo plazmonnogo rezonansa (SPR). S pomoshch'iu in silico modelirovaniia byli predskazany saĭty sviazyvaniia atsetilsalitsilovoĭ kisloty, ibuprofena, khlorpromazina, galoperidola (kotorye po literaturnym dannym proiavliali antimikoticheskuiu aktivnost') v aktivnom tsentre CYP51 Candida albicans i CYP51 Candida glabrata. SPR analiz pozvolil ustanovit' znacheniia Kd kompleksov atsetilsalitsilovoĭ kisloty, ibuprofena i galoperidola s CYP51, kotorye byli v diapazone ot 18 mkM do 126 mkM. Takzhe bylo pokazano, chto strukturnye proizvodnye galoperidola, soderzhashchie razlichnye zamestiteli, mogut pozitsionirovat'sia v aktivnom tsentre CYP51 Candida albicans s vozmozhnym obrazovaniem koordinatsionnykh sviazeĭ mezhdu gidroksil'nymi gruppami proizvodnykh i atomom zheleza v geme CYP51. Takim obrazom, byli predlozheny potentsial'nye bazovye struktury neazol'nykh soedineniĭ, kotorye mogut byt' osnovoĭ dlia sozdaniia novykh ingibitorov CYP51 gribov roda Candida.
Keywords: CYP51 inhibitors; antimycotic; docking; drugs; surface plasmon resonance.
MeSH terms
Substances
LinkOut - more resources
Other Literature Sources