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A computational study of Anthracyclines interacting with lipid bilayers: Correlation of membrane insertion rates, orientation effects and localisation with cytotoxicity

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Title: A computational study of Anthracyclines interacting with lipid bilayers: Correlation of membrane insertion rates, orientation effects and localisation with cytotoxicity
Authors: Gould, I
Toroz, D
Item Type: Journal Article
Abstract: Anthracyclines interact with DNA and topoisomerase II as well as with cell membranes, and it is these latter interactions that can cause an increase in their cytotoxic activity. In the present study a detailed computational analysis of the initial insertion, orientation and nature of the interaction occurring between Anthracyclines and two different lipid bilayers (unsaturated POPC and saturated DMPC) is explored through molecular dynamics (MD) simulations; four Anthracyclines: Doxorubicin (DOX), Epirubicin (EPI), Idarubicin (IDA) and Daunorubicin (DAU) were examined. The results indicate that the increased cytotoxicity of DOX, in comparison to the other three analogues, is correlated with its ability to diffuse at a faster rate into the bilayers. Additionally, DOX exhibited considerably different orientational behaviour once incorporated into the bilayer and exhibited a higher propensity to interact with the hydrocarbon tails in both lipids indicating a higher probability of transport to the other leaflet of the bilayer.
Issue Date: 15-Feb-2019
Date of Acceptance: 23-Jan-2019
URI: http://hdl.handle.net/10044/1/67228
DOI: https://dx.doi.org/10.1038/s41598-019-39411-y
ISSN: 2045-2322
Publisher: Nature Publishing Group
Journal / Book Title: Scientific Reports
Volume: 9
Copyright Statement: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre-ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per-mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 602156
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
STRUCTURAL REQUIREMENTS
MULTIDRUG-RESISTANT
MOLECULAR-DYNAMICS
CARDIOTOXICITY
ADRIAMYCIN
DAUNOMYCIN
ANTIBIOTICS
DOXORUBICIN
KINETICS
EFFLUX
Publication Status: Published
Article Number: ARTN 2155
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences



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