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In Silico Modeling of Isoniazid-Steroid Conjugates Interactions with Mycobacterial Cytochromes P450 and Their Bioconversion in Vitro by the Cells

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Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry Aims and scope Submit manuscript

Abstract—

Molecular docking of four isoniazid hydrazones including steroids dehydroepiandrosterone, pregnenolone, 16α,17α-epoxypregnenolone, and cholestenone (IDHEA, IPRE, IEP5, ICHN), to mycobacterial cytochromes P450 was performed. The in silico study has shown than these hydrazones can be effectively bound to CYP121, CYP124, CYP125, CYP126A1, CYP130, and CYP51 with the calculated binding energy values ranged from –9 kcal/mol to –12 kcal/mol. Calculations also demonstrated that passive lipid bilayer permeability was higher than that of with isoniazid. In vitro IDHEA, IPRE, IEPR were found to undergo bioconversion into their 3-keto-4-en derivatives. This suggests their ability to penetrate into M. tuberculosis H37Rv cells. The results of this study are important in the context of understanding of binding specificity of synthetic steroid derivatives to mycobacterial CYPs and indicate the possibility of using these steroid compounds as new ligands for these enzymes.

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ACKNOWLEDGMENTS

The authors are grateful to the staff of the Department of Radiation Chemistry and Chemical-Pharmaceutical Technologies and the Department of Organic Chemistry (Faculty of Chemistry, Belarusian State University) for the opportunity to perform mass spectrometric and IR spectroscopic analysis.

Funding

This work was supported by the Belarusian Foundation for Basic Research (project no. B18MS-026).

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Authors and Affiliations

  1. Faculty of Chemistry, Belarusian State University, ul. Leningradskaya 14, 220030, Minsk, Belarus

    Y. V. Faletrov, K. A. Gilep, A. S. Falchevskaya, M. S. Horetski, J. V. Panada, E. V. Andrievskaya, E. V. Rudaya & V. M. Shkumatov

  2. Research Institute for Physical Chemical Problems, Belarusian State University, ul. Leningradskaya 14, 220030, Minsk, Belarus

    Y. V. Faletrov, M. S. Horetski, J. V. Panada, N. S. Frolova & V. M. Shkumatov

  3. Institute for Medical Biology, Polish Academy of Sciences, Lodowa str. 106, , 93-232, Lodz, Poland

    A. Brzostek & R. Plocinska

Authors
  1. Y. V. Faletrov
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  2. K. A. Gilep
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  3. A. S. Falchevskaya
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  4. M. S. Horetski
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  5. J. V. Panada
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  6. E. V. Andrievskaya
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  7. E. V. Rudaya
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  8. N. S. Frolova
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  9. A. Brzostek
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  10. R. Plocinska
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  11. V. M. Shkumatov
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Corresponding author

Correspondence to V. M. Shkumatov.

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COMPLIANCE WITH ETHICAL STANDARDS

This article does not contain a description of the research performed by the authors with the participation of humans or the use of animals as research objects.

CONFLICT OF INTEREST

K.A. Gilep and A.S. Falchevskaya participated in the synthesis of the studied hydrazones and testing the interaction with CYP125 as a part of their graduation theses at the Faculty of Chemistry of BSU in 2019 under supervision by V.M. Shkumatov and Ya.V. Faletrov, respectively. The authors are grateful to Dr. A.A. Gilep for constant help in isolation of a purified mycobacterial CYP125 preparation. Other authors postulate the absence of potential conflicts associated with the publication of this material.

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Translated by A. Medvedev

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Faletrov, Y.V., Gilep, K.A., Falchevskaya, A.S. et al. In Silico Modeling of Isoniazid-Steroid Conjugates Interactions with Mycobacterial Cytochromes P450 and Their Bioconversion in Vitro by the Cells. Biochem. Moscow Suppl. Ser. B 15, 111–118 (2021). https://doi.org/10.1134/S1990750821020037

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