Distributions of Therapeutically Promising Steroids in Cellular Membranes

Kamila Riedlová, Michaela Nekardová, Petr Kačer, Kamila Syslová, Mario Vazdar, Pavel Jungwirth, Eva Kudová, Lukasz Cwiklik

    Research output: Contribution to journalArticleScientificpeer-review

    2 Citations (Scopus)

    Abstract

    Abstract Interactions of two neurosteroids, inhibiting membrane-bound N-Methyl-d-aspartate receptors, with phospholipid membranes are studied. Namely, endogenous pregnanolone sulfate is compared with pregnanolone glutamate, the latter being a novel synthetic steroidal inhibitor of these receptors with potential pharmaceutical use. Molecular-level details of steroid-phospholipid membranes interactions are scrutinized employing molecular dynamics simulations supported by quantum chemical calculations to assess steroid lipophilicity. Moreover, permeability of both species across membranes is experimentally evaluated by immobilized artificial membrane chromatography. We demonstrate that while there is no significant difference of lipophilicity and membrane permeability between the two sterols, they differ significantly regarding detailed localization in phospholipid membranes. The bulky glutamate moiety of pregnanolone glutamate is flexible and well exposed to the water phase while the sulfate group of pregnanolone sulfate is hidden in the membrane headgroup region. This dissimilarity of behavior in membranes can potentially account for the observed different activities of the two sterols toward membrane-bound N-Methyl-d-aspartate receptors.
    Original languageEnglish
    Pages (from-to)78-86
    Number of pages8
    JournalChemistry and Physics of Lipids
    Volume203
    Early online date30 Dec 2016
    DOIs
    Publication statusPublished - Mar 2017
    Publication typeA1 Journal article-refereed

    Keywords

    • steroids
    • N-Methyl-d-aspartate receptors
    • membranes
    • molecular dynamics
    • chromatography

    Publication forum classification

    • Publication forum level 1

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