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.
Proveden doking gidrazonov izoniazida, vkliuchaia steroidy degidroépiandrosteron, pregnenolon, 16α,17α-épokipregnenolon i kholestenon (IDHEA, IPRE, IEP5, ICHN), po otnosheniiu k tsitokhromam P450 (CYP) mikobakteriĭ. Ustanovleno in silico, chto éti gidrazony mogut éffektivno sviazyvat'sia s CYP121, CYP124, CYP125, CYP126A1, CYP130 i CYP51 c raschetnymi énergiiami sviazyvaniia ot -9 kkal/mol' do -12 kkal/mol'. Pri modelirovanii passivnoĭ diffuzii cherez lipidnyĭ bisloĭ pokazana povyshennaia pronitsaemost' kon"iugatov cherez lipidnye membrany po sravneniiu s samim izoniazidom. V éksperimente in vitro opredeleno, chto veshchestva IDHEA, IPRE, IEPR sposobny prevrashchat'sia v sootvetstvuiushchie 3-keto-4-enovye proizvodnye, chto ukazyvaet na ikh sposobnost' pronikat' v kletki mikobakteriĭ M. tuberculosis H37Rv. Poluchennye dannye vnosiat vklad v ponimanie spetsifichnosti sviazyvaniia iskusstvennykh proizvodnykh steroidov s CYP mikobakteriĭ i svidetel'stvuiut o vozmozhnosti ispol'zovaniia izuchennykh nami steroidnykh soedineniĭ v kachestve novykh ligandov dlia étikh fermentov.
Keywords: conjugates; cytochromes P450; isoniazid; molecular docking; mycobacterium; steroids.