Interactions of a Novel Anthracycline with Oligonucleotide DNA and Cyclodextrins in an Aqueous Environment.

Berubicin, a chemotherapy medication belonging to the class of anthracyclines, is simulated in double-stranded DNA sequences and cyclodextrins in an aqueous environment via full-atom molecular dynamics simulations on the time scale of microseconds. The drug is studied in both the neutral and protonated states so as to better comprehend the role of its charge in the formed complexes. The noncovalent berubicin-DNA and berubicin-cyclodextrin complexes are investigated in detail, paying special attention to their thermodynamic description by employing the double decoupling method, the solvent balance method, the weighted solvent accessible surface model, and the linear interaction energy method. A novel approach for extracting the desolvation thermodynamics of the binding process is also presented. Both the binding and desolvation Gibbs energies are decomposed into entropic and enthalpic contributions so as to elucidate the nature of complexation and its driving forces. Selected structural and geometrical properties of all the complexes, which are all stable, are analyzed. Both cyclodextrins under consideration are widely utilized for drug delivery purposes, and a comparative investigation between their bound states with berubicin is carried out.

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

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 ß-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.

In silico study of levodopa in hydrated lipid bilayers at the atomistic level.

This article presents atomistic molecular dynamics and umbrella sampling simulations of levodopa at various concentrations in hydrated cholesterol-free 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol-containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers. Levodopa is the standard medication for Parkinson's disease and is marketed under various trade names; in the context of this article, the levodopa molecule is mostly studied in its zwitterionic form but some results concerning the neutral levodopa are presented as well for comparison purposes. The motivation is to study in detail how levodopa behaves in different hydrated lipid membranes, primarily from the thermodynamic point of view, and reveal aspects of mechanism of its permeation through them. Dependencies of properties on the levodopa concentration are also investigated. Special attention is paid to the calculation of mass density profiles, order parameters and self-diffusion coefficients. Levodopa zwitterions, which form a hydrogen bond network with water and phospholipid molecules, are found to be preferentially located at the water/lipid interface, as well as in the aqueous phase surrounding the cholesterol-free and cholesterol-containing bilayers. This is concluded from the potentials of mean force calculated by umbrella sampling simulations as levodopa is transferred from the lipid to the aqueous phase along an axis perpendicular to the two leaflets of the membranes.