NDLI: Structural perturbation of a dipalmitoylphosphatidylcholine (DPPC) bilayer by warfarin and its bolaamphiphilic analogue: A molecular dynamics study.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Ayee, Manuela Aseye Ayele Roth, Charles William Akpa, Belinda Sena
Description	Author Affiliation: Ayee MA ( Department of Chemical Engineering, University of Illinois at Chicago, 810 S. Clinton St., Chicago, IL 60607, USA); Roth CW ( Department of Chemical Engineering, University of Illinois at Chicago, 810 S. Clinton St., Chicago, IL 60607, USA. Electronic address: croth6@uic.edu.); Akpa BS ( Department of Chemical Engineering, University of Illinois at Chicago, 810 S. Clinton St., Chicago, IL 60607, USA)
Abstract	Compounds with nominally similar biological activity may exhibit differential toxicity due to differences in their interactions with cell membranes. Many pharmaceutical compounds are amphiphilic and can be taken up by phospholipid bilayers, interacting strongly with the lipid-aqueous interface whether or not subsequent permeation through the bilayer is possible. Bolaamphiphilic compounds, which possess two hydrophilic ends and a hydrophobic linker, can likewise undergo spontaneous uptake by bilayers. While membrane-spanning bolaamphiphiles can stabilize membranes, small molecules with this characteristic have the potential to create membrane defects via disruption of bilayer structure and dynamics. When compared to the amphiphilic therapeutic anticoagulant, warfarin, the bolaamphiphilic analogue, brodifacoum, exhibits heightened toxicity that goes beyond superior inhibition of the pharmacological target enzyme. We explore, herein, the consequences of anticoagulant accumulation in a dipalmitoylphosphatidylcholine (DPPC) bilayer. Coarse-grained molecular dynamics simulations reveal that permeation of phospholipid bilayers by brodifacoum causes a disruption of membrane barrier function that is driven by the bolaamphiphilic nature and size of this molecule. We find that brodifacoum partitioning into bilayers causes membrane thinning and permeabilization and promotes lipid flip-flop - phenomena that are suspected to play a role in triggering cell death. These phenomena are either absent or less pronounced in the case of the less toxic, amphiphilic compound, warfarin.
ISSN	00219797
Journal	Journal of Colloid and Interface Science
Volume Number	468
e-ISSN	10957103
Language	English
Publisher	Elsevier
Publisher Date	2016-04-15
Publisher Place	United States
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Discipline Colloid & Interface Science
Content Type	Text
Resource Type	Article
Subject	Surfaces, Coatings and Films Colloid and Surface Chemistry Biomaterials Electronic, Optical and Magnetic Materials

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