Molecular simulations of doxorubicin complexed with native and modified cyclodextrins in water

Abstract

In this study, all-atom molecular dynamics simulations have been performed to investigate from a nanoscopic point of view the interactions in supramolecular complexes formed between doxorubicin and cyclodextrins in an aqueous phase at a temperature of 310 K. All the simulations are on the time scales of microseconds and are carried out on High Performance Computing resources provided by the Greek Supercomputer ARIS. Doxorubicin, which is a well-known anticancer drug belonging to the class of anthracyclines, is simulated with two cyclodextrins of broad utilization in drug delivery, i.e.: γ-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin. In both cases, the complexation process takes place spontaneously during the course of the simulations and a detailed analysis of the formed complexes is conducted in terms of structural, dynamical and thermodynamic properties. In addition, we present a quantitative analysis of how doxorubicin affects, upon complexation, the geometry, the hydrogen bonding network and the hydration of the selected cyclodextrins. Special attention is paid to the thermodynamic description of the simulated systems. More specifically, the standard binding free energy is calculated with an extended version of the linear interaction energy method. The presented in silico approach reveals that doxorubicin forms stable complexes with the chosen cyclodextrin molecules, there is a water solubility enhancement of the drug with respect to its unbound state and also cyclodextrins act protectively to the drug preventing undesired effects, such as the glycosidic degradation. Excellent agreement is found between the presented results and published in silico and experimental findings.