TY - JOUR
T1 - Assessing the Perturbing Effects of Drugs on Lipid Bilayers Using Gramicidin Channel-Based in Silico and in Vitro Assays
AU - Sun, Delin
AU - Peyear, Thasin A.
AU - Bennett, W. F.Drew
AU - Holcomb, Matthew
AU - He, Stewart
AU - Zhu, Fangqiang
AU - Lightstone, Felice C.
AU - Andersen, Olaf S.
AU - Ingólfsson, Helgi I.
N1 - Funding Information:
This work was funded by Laboratory Directed Research and Development at the Lawrence Livermore National Laboratory (18-ERD-035). We thank the Livermore Institutional Grand Challenge for the computing time. This work was performed under the auspices of the U.S. DOE by the Lawrence Livermore National Laboratory under contract DE-AC52-07NA27344. O.S.A. is the recipient of NIH grant R01 GM021342. Release LLNL-JRNL-807837.
PY - 2020/10/22
Y1 - 2020/10/22
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.0c00958
DO - 10.1021/acs.jmedchem.0c00958
M3 - Article
C2 - 32945672
AN - SCOPUS:85094220330
VL - 63
SP - 11809
EP - 11818
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 20
ER -