Molecular simulations of fluoxetine in hydrated lipid bilayers, as well as in aqueous solutions containing β-cyclodextrin

Abstract

Fluoxetine, which is a well-known antidepressant drug, is studied in hydrated cholesterol-free and cholesterol-containing lipid bilayers through unbiased and biased atomistic molecular dynamics simulations. The latter are conducted for the calculation of the potential of mean force (PMF) of fluoxetine along an axis perpendicular to the two leaflets of the bilayer. The PMF indicates that the drug prefers to reside inside the lipid phase and allows us to calculate important thermodynamic properties, such as the Gibbs energy difference of partitioning from the water to the lipid phase and the Gibbs energy barrier for hopping events between the two leaflets of the bilayer. The results from the biased simulations are in accord with the mass density profiles calculated from the unbiased simulations. Moreover, we estimate the effect of fluoxetine mole fraction on the order parameters of the lipid alkyl chains and on the area per lipid. It is also found that fluoxetine forms a hydrogen bond network with lipids and water molecules penetrating into the lipid phase. In addition, fluoxoetine is studied in detail in aqueous solutions containing β-cyclodextrin. It is observed from unbiased molecular dynamics simulations that the two aforementioned molecules form a noncovalent complex spontaneously and the calculated binding free energy is in agreement with the literature. © 2022 Elsevier Inc.