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The Effect of Warfarin’s Structural Diversity on Permeation Across a DPPC Bilayer Membrane
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. (BBCL)ORCID iD: 0000-0002-7392-0591
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. (BBCL)ORCID iD: 0000-0003-4037-1992
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. (BBCL)
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. (BBCL)ORCID iD: 0000-0002-0407-6542
2010 (English)Conference paper, Published paper (Refereed)
Abstract [en]

Warfarin is an oral anticoagulant drug used to prevent thrombolic disorders such as myocardial infarction and stroke by inhibiting the active site of vitamin-K dependent epoxide reductase (VKOR) [1]. Despite being in widespread use and having a narrow therapeutic window, its mechanisms of action are not yet fully understood and incorrect warfarin dosage often leads to severe side effects. A factor limiting our understanding of warfarin’s bioavailability is warfarin’s structural diversity, which has been shown to be strongly affected by the nature of molecular environment e.g. solvent polarity and pH [2-7]. One of the major factors contributing to a drug’s biological effect is membrane transport, a process involving exposure of warfarin to environments of quite different character. Since a drug’s transport across membrane may include both active transport by carriers as well as diffusion-controlled processes, it may be envisaged that in order to fully predict warfarin’s anticoagulant effect these mechanisms must be carefully elucidated.

 

Molecular dynamics (MD) simulations have previously been performed in order to obtain detailed information on static equilibrium as well as dynamic properties of small organic drugs in biomembranes. One of the most studied lipids in cell membrane simulations has been dipalmitoylphosphatidylcholine (DPPC) which is the most abundant phospholipid in cell membranes. Here we present lipid bilayer membrane transport properties for a series of warfarin structures previously reported in the literature using a fully solvated DPPC membrane model. Data extracted from simulations shed light on differences in membrane partioning as well as mobilities of warfarin isomers studied and a mechanism by which warfarin permeates through membranes in vivo is presented.

 

References

  1. Landefeld, C.; Beyth, R. Am. J. Med. 1993, 95, 315-328.
  2. Karlsson, B. C. G.; Rosengren, A. M.; Andersson, P. O.; Nicholls, I. A. J. Phys. Chem. B 2007, 111, 10520-10528.
  3. Karlsson, B. C. G.; Rosengren, A. M.; Andersson, P. O.; Nicholls, I. A. J. Phys. Chem. B 2009, 113, 7945-7949.
  4. Karlsson, B. C. G.; Rosengren, A. M.; Näslund, I.; Andersson, P. O.; Nicholls, I. A. Submitted 2010.
  5. Rosengren, A. M.; Karlsson, B. C. G.; Näslund, I.; Andersson, P. O.; Nicholls, I. A. Submitted 2010.
  6. Nicholls, I. A.; Karlsson, B. C. G.; Rosengren, A. M.; Henschel, H. J. Mol. Recognit. 2010, In press.
  7. Henschel, H.; Karlsson, B. C. G.; Rosengren, A. M.; Nicholls, I. A. Submitted 2010.

 

Place, publisher, year, edition, pages
2010.
National Category
Organic Chemistry
Research subject
Natural Science, Organic Chemistry
Identifiers
URN: urn:nbn:se:lnu:diva-6719OAI: oai:DiVA.org:lnu-6719DiVA, id: diva2:329032
Conference
8th European Conference on Computational Chemistry, Lund
Available from: 2010-07-07 Created: 2010-07-07 Last updated: 2016-11-11Bibliographically approved

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Karlsson, Björn C. G.Olsson, Gustaf D.Rosengren, Annika M.Nicholls, Ian A.

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