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Titel: Cooperative Effects of an Antifungal Moiety and DMSO on Pore Formation over Lipid Membranes Revealed by Free Energy Calculations
VerfasserIn: Kasparyan, Gari
Poojari, Chetan
Róg, Tomasz
Hub, Jochen S.
Sprache: Englisch
Titel: The Journal of Physical Chemistry. B
Bandnummer: 124
Heft: 40
Seiten: 8811-8821
Verlag/Plattform: ACS
Erscheinungsjahr: 2020
Freie Schlagwörter: Defects
Free Energy
Lipids
Membranes
Molecules
DDC-Sachgruppe: 500 Naturwissenschaften
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: Itraconazole is a triazole drug widely used in the treatment of fungal infections, and it is in clinical trials for treatment of several cancers. However, the drug suffers from poor solubility, while experiments have shown that itraconazole delivery in liposome nanocarriers improves both circulation half-life and tissue distribution. The drug release mechanism from the nanocarrier is still unknown, and it depends on several factors including membrane stability against defect formation. In this work, we used molecular dynamics simulations and potential of mean force (PMF) calculations to quantify the influence of itraconazole on pore formation over lipid membranes, and we compared the effect by itraconazole with a pore-stabilizing effect by the organic solvent dimethyl sulfoxide (DMSO). According to the PMFs, both itraconazole and DMSO greatly reduce the free energy of pore formation, by up to ∼20 kJ mol−1 . However, whereas large concentrations of itraconazole of 8 mol % (relative to lipid) were required, only small concentrations of a few mole % DMSO (relative to water) were sufficient to stabilize pores. In addition, itraconazole and DMSO facilitate pore formation by different mechanisms. Whereas itraconazole predominantly aids the formation of a partial defect with a locally thinned membrane, DMSO mainly stabilizes a transmembrane water needle by shielding it from the hydrophobic core. Notably, the two distinct mechanisms act cooperatively upon adding both itraconazole and DMSO to the membrane, as revealed by an additional reduction of the pore free energy. Overall, our simulations reveal molecular mechanisms and free energies of membrane pore formation by small molecules. We suggest that the stabilization of a locally thinned membrane as well as the shielding of a transmembrane water needle from the hydrophobic membrane core may be a general mechanism by which amphiphilic molecules facilitate pore formation over lipid membranes at sufficient concentrations.
DOI der Erstveröffentlichung: 10.1021/acs.jpcb.0c03359
URL der Erstveröffentlichung: https://pubs.acs.org/doi/10.1021/acs.jpcb.0c03359
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-434576
hdl:20.500.11880/38957
http://dx.doi.org/10.22028/D291-43457
ISSN: 1520-5207
1520-6106
Datum des Eintrags: 14-Nov-2024
Bezeichnung des in Beziehung stehenden Objekts: Supporting Information
In Beziehung stehendes Objekt: https://ndownloader.figstatic.com/files/24816767
Fakultät: NT - Naturwissenschaftlich- Technische Fakultät
Fachrichtung: NT - Physik
Professur: NT - Prof. Dr. Jochen Hub
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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