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Distributions of therapeutically promising neurosteroids in cellular membranes

K. Riedlová, M. Nekardová, P. Kačer, K. Syslová, M. Vazdar, P. Jungwirth, E. Kudová, L. Cwiklik,

. 2017 ; 203 (-) : 78-86. [pub] 20161230

Jazyk angličtina Země Irsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc17023390

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 steroids, 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 steroids toward membrane-bound N-Methyl-d-aspartate receptors.

Citace poskytuje Crossref.org

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$a Interactions of two neurosteroids, inhibiting membrane-bound N-Methyl-d-aspartate receptors, with phospholipid membranes are studied. Namely, endogenous pregnanolone sulfate is compared with pregnanolone glutamate, the latter being a novel synthetic steroidal inhibitor of these receptors with potential pharmaceutical use. Molecular-level details of steroid-phospholipid membranes interactions are scrutinized employing molecular dynamics simulations supported by quantum chemical calculations to assess steroid lipophilicity. Moreover, permeability of both species across membranes is experimentally evaluated by immobilized artificial membrane chromatography. We demonstrate that while there is no significant difference of lipophilicity and membrane permeability between the two steroids, they differ significantly regarding detailed localization in phospholipid membranes. The bulky glutamate moiety of pregnanolone glutamate is flexible and well exposed to the water phase while the sulfate group of pregnanolone sulfate is hidden in the membrane headgroup region. This dissimilarity of behavior in membranes can potentially account for the observed different activities of the two steroids toward membrane-bound N-Methyl-d-aspartate receptors.
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$a Nekardová, Michaela $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 16610 Prague 6, Czech Republic; Faculty of Mathematics and Physics, Charles University in Prague, Ke Karlovu 3, Prague 2, 121 16, Czech Republic.
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$a Kačer, Petr $u University of Chemistry and Technology, Technicka 5, 16610 Prague 6, Czech Republic.
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$a Syslová, Kamila $u University of Chemistry and Technology, Technicka 5, 16610 Prague 6, Czech Republic.
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$a Vazdar, Mario $u Rudjer Bošković Institute, Division of Organic Chemistry and Biochemistry, POB 180, HR-10002 Zagreb, Croatia.
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$a Jungwirth, Pavel $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 16610 Prague 6, Czech Republic; Department of Physics, Tampere University of Technology, P. O. Box 692, FI-33101 Tampere, Finland.
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$a Kudová, Eva $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 16610 Prague 6, Czech Republic. Electronic address: kudova@uochb.cas.cz.
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$a Cwiklik, Lukasz $u J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, Dolejškova 3, 182 23 Prague, Czech Republic. Electronic address: lukasz.cwiklik@jh-inst.cas.cz.
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