In silico modeling of izoniazid-steroid conjugates interactions with cytochromes P450 of mycobacteria and their bioconversion in vitro by the cells

   
Faletrov Y.V.1, Gilep K.A.2, Falchevskaya A.S.2, Horetski M.S.1, Panada J.V.1, Andrievskaya E.V.2, Rudaya E.V.3, Frolova N.S.3, Brzostek A.4, Plocinska R.4, Shkumatov V.M.1

1. Faculty of Chemistry, Belarusian State University, Minsk, Belarus; Research Institute for Physical Chemical Problems, Belarusian State University, Minsk, Belarus
2. Faculty of Chemistry, Belarusian State University, Minsk, Belarus
3. Research Institute for Physical Chemical Problems, Belarusian State University, Minsk, Belarus
4. Institute for Medical Biology, Polish Academy of Sciences, Lodz, Poland
Section: Experimental Study
DOI: 10.18097/PBMC20206605378      PubMed Id: 33140731
Year: 2020  Volume: 66  Issue: 5  Pages: 378-385
Molecular docking of four hydrazones of isoniazid with steroids (dehydroepiandrosterone, pregnenolone, 16α,17α-epoxypregnenolone, 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 binding energy ranged from -9 kcal/mol to -12 kcal/mol. Calculations also demonstrated enhancement of passive lipid bilayer permeability with respect to 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 specificity of binding of synthetic steroid derivatives to mycobacterial CYPs and indicate the possibility of using the steroid compounds studied by us as new ligands for these enzymes.
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Keywords: isoniazid, steroids, conjugates, molecular docking, mycobacterium, cytochromes P450
Citation:

Faletrov, Y. V., Gilep, K. A., Falchevskaya, A. S., Horetski, M. S., Panada, J. V., Andrievskaya, E. V., Rudaya, E. V., Frolova, N. S., Brzostek, A., Plocinska, R., Shkumatov, V. M. (2020). In silico modeling of izoniazid-steroid conjugates interactions with cytochromes P450 of mycobacteria and their bioconversion in vitro by the cells. Biomeditsinskaya khimiya, 66(5), 378-385.
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