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

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Abstract

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 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 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.

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REFERENCES

  1. Pappas, P.G., Kauffman, C.A., Andes, D.R., Clancy, C.J., Marr, K.A., Ostrosky-Zeichner, L., Reboli, A.C., Schuster, M.G., Vazquez, J.A., Walsh, T.J., Zaoutis, T.E., and Sobel, J.D., Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am., 2016, vol. 62, pp. e1-50. https://doi.org/10.1093/cid/civ933

    Article  Google Scholar 

  2. Warrilow, A.G., Parker, J.E., Kelly, D.E., and Kelly, S.L., Antimicrob. Agents Chemother., 2013, vol. 57, pp. 1352–1360. https://doi.org/10.1128/AAC.02067-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang, F.-J., Zhang, D., Liu, Z.-H., Wu, W.-X., Bai, H.-H., and Dong, H.-Y., Chin. Med. J. (Engl.), 2016, vol. 129, pp. 1161–1165. https://doi.org/10.4103/0366-6999.181964

    Article  CAS  Google Scholar 

  4. Masamrekh, R., Kuzikov, A., Veselovsky, A., Toropygin, I., Shkel, T., Strushkevich, N., Gilep, A., Usanov, S., Archakov, A., and Shumyantseva, V., J. Inorg. Biochem., 2018, vol. 186, pp. 24–33. https://doi.org/10.1016/j.jinorgbio.2018.05.010

    Article  CAS  PubMed  Google Scholar 

  5. Afeltra, J. and Verweij, P.E., Eur. J. Clin. Microbiol. Infect. Dis. Off. Publ. Eur. Soc. Clin. Microbiol., 2003, vol. 22, pp. 397–407. https://doi.org/10.1007/s10096-003-0947-x

    Article  CAS  Google Scholar 

  6. Stylianou, M., Kulesskiy, E., Lopes, J.P., Granlund, M., Wennerberg, K., and Urban, C.F., Antimicrob. Agents Chemother., 2014, vol. 58, pp. 1055–1062. https://doi.org/10.1128/AAC.01087-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lagunin, A., Stepanchikova, A., Filimonov, D., and Poroikov, V., Bioinformatics, 2000, vol. 16, pp. 747–748. https://doi.org/10.1093/bioinformatics/16.8.747

    Article  CAS  PubMed  Google Scholar 

  8. Shkel, T.V., Vasilevskaya, A.V., Gilep, A.A., Usanov, S.A., Chernovetsky, M.A., and Lukyanea’ko, I.G., Dokl. Nat. Akad. Nauk Belarus, 2017, vol. 56, pp. 64–71.

    Google Scholar 

  9. Shkel, T.V., Grabovec, I.P., Gilep, A.A., Varaksa, T.S., Strushkevich, N.V., Dolgopalets, V.I., and Charnou, Y.G., Proc. Natl. Acad. Sci. Belarus Chem. Ser., 2019, vol. 54, pp. 450–454. https://doi.org/10.29235/1561-8331-2018-54-4-450-454

    Article  CAS  Google Scholar 

  10. Kim, J.H., Chan, K.L., Cheng, L.W., Tell, L.A., Byrne, B.A., Clothier, K., and Land, K.M., Methods Protoc., 2019, vol. 2, 31. https://doi.org/10.3390/mps2020031

    Article  CAS  PubMed Central  Google Scholar 

  11. Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., and Ferrin, T.E., J. Comput. Chem., 2004, vol. 25, pp. 1605–1612. https://doi.org/10.1002/jcc.20084

    Article  CAS  PubMed  Google Scholar 

  12. Grosdidier, A., Zoete, V., and Michielin, O., Nucl. Acids Res., 2011, vol. 39, pp. W270–W277. https://doi.org/10.1093/nar/gkr366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Grosdidier, A., Zoete, V., and Michielin, O., J. Comput. Chem., 2011, vol. 32, pp. 2149–2159. https://doi.org/10.1002/jcc.21797

    Article  CAS  PubMed  Google Scholar 

  14. Zoete, V., Daina, A., Bovigny, C., and Michielin, O., J. Chem. Inf. Model., 2016, vol. 56, pp. 1399–1404. https://doi.org/10.1021/acs.jcim.6b00174

    Article  CAS  PubMed  Google Scholar 

  15. Wang, M.-Y., Wang, F., Hao, G.-F., and Yang, G.-F., J. Agric. Food Chem., 2019, vol. 67, pp. 1823–1830. https://doi.org/10.1021/acs.jafc.8b06596

    Article  CAS  PubMed  Google Scholar 

  16. Backman, T.W.H., Cao, Y., and Girke, T., Nucl. Acids Res., 2011, vol. 39, pp. W486–W491. https://doi.org/10.1093/nar/gkr320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Goddard, T.D., Huang, C.C., Meng, E.C., Pettersen, E.F., Couch, G.S., Morris, J.H., and Ferrin, T.E., Protein Sci. Publ. Protein Soc., 2018, vol. 27, pp. 14–25. https://doi.org/10.1002/pro.3235

    Article  CAS  Google Scholar 

  18. Preissner, S., Kroll, K., Dunkel, M., Senger, C., Goldsobel, G., Kuzman, D., Guenther, S., Winnenburg, R., Schroeder, M., and Preissner, R., Nucl. Acids Res., 2010, vol. 38, pp. D237–D243. https://doi.org/10.1093/nar/gkp970

    Article  CAS  PubMed  Google Scholar 

  19. Ji, C., Liu, N., Tu, J., Li, Z., Han, G., Li, J., and Sheng, C., ACS Infect. Dis., 2020, vol. 6, pp. 768–786. https://doi.org/10.1021/acsinfecdis.9b00197

    Article  CAS  PubMed  Google Scholar 

  20. Schenkman, J.B., Remmer, H., and Estabrook, R.W., Mol. Pharmacol., 1967, vol. 3, pp. 113–123.

    CAS  PubMed  Google Scholar 

  21. von Kries, J.P., Warrier, T., and Podust, L.M., Curr. Protoc. Microbiol., 2010, Chapter 17, Unit 17.4. https://doi.org/10.1002/9780471729259.mc1704s16

  22. Shahrokh, K., Orendt, A., Yost, G.S., and Cheatham, T.E., J. Comput. Chem., 2012, vol. 33, pp. 119–133. https://doi.org/10.1002/jcc.21922

    Article  CAS  PubMed  Google Scholar 

  23. Schlichting, I., Berendzen, J., Chu, K., Stock, A.M., Maves, S.A., Benson, D.E., Sweet, R.M., Ringe, D., Petsko, G.A., and Sligar, S.G., Science, 2000, vol. 287, pp. 1615–1622. https://doi.org/10.1126/science.287.5458.1615

    Article  CAS  PubMed  Google Scholar 

  24. Chen, S.-H., Sheng, C.-Q., Xu, X.-H., Jiang, Y.-Y., Zhang, W.-N., and He, C., Biol. Pharm. Bull., 2007, vol. 30, pp. 1246–1253. https://doi.org/10.1248/bpb.30.1246

    Article  CAS  PubMed  Google Scholar 

  25. Siqueira, T.H. and Martínez, L., J. Biomol. Struct. Dyn., 2020, vol. 38, pp. 1659–1669. https://doi.org/10.1080/07391102.2019.1614998

    Article  CAS  Google Scholar 

  26. Gervasini, G., Caballero, M.J., Carrillo, J.A., and Benitez, J., ISRN Pharmacol., 2013, vol. 2013, 792456. https://doi.org/10.1155/2013/792456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tani, N., Rahnasto-Rilla, M., Wittekindt, C., Salminen, K.A., Ritvanen, A., Ollakka, R., Koskiranta, J., Raunio, H., and Juvonen, R.O., Eur. J. Med. Chem., 2012, vol. 47, pp. 270–277. https://doi.org/10.1016/j.ejmech.2011.10.053

    Article  CAS  PubMed  Google Scholar 

  28. Lv, Z., Sheng, C., Zhang, Y., Wang, T., Feng, J., Sun, H., Zhong, H., Zhang, M., Chen, H., and Li, K. Bioorg. Med. Chem. Lett., 2010, vol. 20, pp. 7106–7109. https://doi.org/10.1016/j.bmcl.2010.09.072

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Bioinformatic analysis and computer modeling were done in the framework of the Russian Federation fundamental research program for the long-term period for 2021−2030. SPR studies were supported by the Russian Foundation for Basic Research (RFBR; project grant no. 20-04-00014), using the equipment of “Human Proteome” Core Facility of the Institute of Biomedical Chemistry (funded by the Russian Ministry of Science and Education, Agreement no. 075-15-2019-1502 of September 5, 2019).

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Authors and Affiliations

  1. Institute of Biomedical Chemistry, ul. Pogodinskaya 10, 119121, Moscow, Russia

    L. A. Kaluzhskiy, P. V. Ershov, E. O. Yablokov, Y. V. Mezentsev, O. V. Gnedenko & A. S. Ivanov

  2. Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus, ul. Kuprevicha 5, bldg. 2, 220141, Minsk, Belarus

    T. V. Shkel, A. A. Gilep & S. A. Usanov

Authors
  1. L. A. Kaluzhskiy
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  2. P. V. Ershov
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  3. E. O. Yablokov
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  4. Y. V. Mezentsev
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  5. O. V. Gnedenko
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  6. T. V. Shkel
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  7. A. A. Gilep
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  8. S. A. Usanov
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  9. A. S. Ivanov
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Correspondence to L. A. Kaluzhskiy.

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The authors declare that they have no conflicts of interest. This work does not contain any research using humans and animals as research objects.

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Supplementary materials are available in the electronic version of the article on the journal website (http://pbmc.ibmc.msk.ru).

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Translated by A. Medvedev

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Kaluzhskiy, L.A., Ershov, P.V., Yablokov, E.O. et al. Screening of Potential Non-Azole Inhibitors of Lanosterol 14-Alpha Demethylase (CYP51) of the Сandida Fungi. Biochem. Moscow Suppl. Ser. B 15, 215–223 (2021). https://doi.org/10.1134/S1990750821030045

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