Assessing the Perturbing Effects of Drugs on Lipid Bilayers Using Gramicidin Channel-Based In Silico and In Vitro Assays
Abstract
Partitioning of bioactive molecules, including drugs, into cell membranes may produce indiscriminate changes in membrane protein function. As a guide to safe drug development, it therefore becomes important to be able to predict the bilayer-perturbing potency of hydrophobic/amphiphilic drugs candidates. Toward this end, we exploited gramicidin channels as molecular force probes and developed in silico and in vitro assays to measure drugs’ bilayer-modifying potency. We examined eight drug-like molecules that were found to enhance or suppress gramicidin channel function in a thick 1,2-dierucoyl-sn-glycero-3-phosphocholine (DC22:1PC) but not in thin 1,2-dioleoyl-sn-glycero-3-phosphocholine (DC18:1PC) lipid bilayer. The mechanism underlying this difference was attributable to the changes in gramicidin dimerization free energy by drug-induced perturbations of lipid bilayer physical properties and bilayer–gramicidin interactions. The combined in silico and in vitro approaches, which allow for predicting the perturbing effects of drug candidates on membrane protein function, have implications for preclinical drug safety assessment.
- Authors:
-
- Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York 10065, United States
- Publication Date:
- Research Org.:
- Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); USDOE National Nuclear Security Administration (NNSA)
- OSTI Identifier:
- 1669192
- Alternate Identifier(s):
- OSTI ID: 1683620; OSTI ID: 1813710
- Report Number(s):
- LLNL-JRNL-807837
Journal ID: ISSN 0022-2623
- Grant/Contract Number:
- 18-ERD-035; AC52-07NA27344; R01 GM021342
- Resource Type:
- Published Article
- Journal Name:
- Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Name: Journal of Medicinal Chemistry Journal Volume: 63 Journal Issue: 20; Journal ID: ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; vesicles; monomers; fluorescence; oligomers; molecules; 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Sun, Delin, Peyear, Thasin A., Bennett, W. F. Drew, Holcomb, Matthew, He, Stewart, Zhu, Fangqiang, Lightstone, Felice C., Andersen, Olaf S., and Ingólfsson, Helgi I. Assessing the Perturbing Effects of Drugs on Lipid Bilayers Using Gramicidin Channel-Based In Silico and In Vitro Assays. United States: N. p., 2020.
Web. doi:10.1021/acs.jmedchem.0c00958.
Sun, Delin, Peyear, Thasin A., Bennett, W. F. Drew, Holcomb, Matthew, He, Stewart, Zhu, Fangqiang, Lightstone, Felice C., Andersen, Olaf S., & Ingólfsson, Helgi I. Assessing the Perturbing Effects of Drugs on Lipid Bilayers Using Gramicidin Channel-Based In Silico and In Vitro Assays. United States. https://doi.org/10.1021/acs.jmedchem.0c00958
Sun, Delin, Peyear, Thasin A., Bennett, W. F. Drew, Holcomb, Matthew, He, Stewart, Zhu, Fangqiang, Lightstone, Felice C., Andersen, Olaf S., and Ingólfsson, Helgi I. Fri .
"Assessing the Perturbing Effects of Drugs on Lipid Bilayers Using Gramicidin Channel-Based In Silico and In Vitro Assays". United States. https://doi.org/10.1021/acs.jmedchem.0c00958.
@article{osti_1669192,
title = {Assessing the Perturbing Effects of Drugs on Lipid Bilayers Using Gramicidin Channel-Based In Silico and In Vitro Assays},
author = {Sun, Delin and Peyear, Thasin A. and Bennett, W. F. Drew and Holcomb, Matthew and He, Stewart and Zhu, Fangqiang and Lightstone, Felice C. and Andersen, Olaf S. and Ingólfsson, Helgi I.},
abstractNote = {Partitioning of bioactive molecules, including drugs, into cell membranes may produce indiscriminate changes in membrane protein function. As a guide to safe drug development, it therefore becomes important to be able to predict the bilayer-perturbing potency of hydrophobic/amphiphilic drugs candidates. Toward this end, we exploited gramicidin channels as molecular force probes and developed in silico and in vitro assays to measure drugs’ bilayer-modifying potency. We examined eight drug-like molecules that were found to enhance or suppress gramicidin channel function in a thick 1,2-dierucoyl-sn-glycero-3-phosphocholine (DC22:1PC) but not in thin 1,2-dioleoyl-sn-glycero-3-phosphocholine (DC18:1PC) lipid bilayer. The mechanism underlying this difference was attributable to the changes in gramicidin dimerization free energy by drug-induced perturbations of lipid bilayer physical properties and bilayer–gramicidin interactions. The combined in silico and in vitro approaches, which allow for predicting the perturbing effects of drug candidates on membrane protein function, have implications for preclinical drug safety assessment.},
doi = {10.1021/acs.jmedchem.0c00958},
journal = {Journal of Medicinal Chemistry},
number = 20,
volume = 63,
place = {United States},
year = {Fri Sep 18 00:00:00 EDT 2020},
month = {Fri Sep 18 00:00:00 EDT 2020}
}
https://doi.org/10.1021/acs.jmedchem.0c00958
Figures / Tables:
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