Modelling the effect of BSEP inhibitors in lipid bilayers by means of all atom Molecular Dynamics (MD) simulation

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Title: Modelling the effect of BSEP inhibitors in lipid bilayers by means of all atom Molecular Dynamics (MD) simulation
Authors: Toroz, D
Khanna, T
Gould, I
Item Type: Journal Article
Abstract: The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. Genetically inherited defects in BSEP expression or activity causes cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo, suggesting this could be one of the mechanisms that initiates human DILI. The relationship between BSEP inhibition and molecular physicochemical properties has been previously investigated identifying calculated lipophilicity and molecular weight to be significantly correlated with BSEP inhibition. Predictive BSEP classification models, constructed through multiple quantitative structure-activity relationship modeling approaches, exhibit significant anomalies with differences in experimental IC50 values of three orders of magnitude for molecules of the same calculated lipophilicity and molecular weight. The interaction of these molecules with the lipid bilayer membrane has been identified as a major contributory factor to BSEP inhibition. In this study we apply unbiased molecular dynamics (MD) simulations to study the permeation times as well as orientation preferences of BSEP inhibitors in two different lipids (saturated DMPC and unsaturated POPC). The simulations reveal that strong BSEP inhibitors have the slowest permeation times, in both POPC and DMPC, with a secondary conclusion that the time of permeation is more rapid in POPC than DMPC. The orientation of the molecules in the membrane reveals strong correlation with chemical structure, molecules containing only hydroxyl and carboxylic groups orient themselves perpendicular to the membrane whereas molecules containing nitrogen atoms exhibit no orientational preference in respect of the membrane. Finally, H-bonding interactions computed between the molecules and the membrane reveal the specific location of the molecules within the membrane.
Issue Date: 28-Feb-2019
Date of Acceptance: 8-Jan-2019
ISSN: 2470-1343
Publisher: American Chemical Society
Start Page: 3341
End Page: 3350
Journal / Book Title: ACS Omega
Volume: 4
Issue: 2
Copyright Statement: © 2019 American Chemical Society. This is an open access article published under an ACS AuthorChoice License ( ), which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Publisher version:
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 602156
Keywords: Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Publication Status: Published
Online Publication Date: 2019-02-14
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences

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