Influence of Ethanol as a Co-Solvent in Cyclodextrin Inclusion Complexation: A Molecular Dynamics Study

Molecular dynamics (MD) simulations were used to investigate the dynamics and host-guest interactions of the inclusion complexes between a potent anti-HIV agent, UC781, and three different types of cyclodextrins (CDs) including beta CD, 2,6-dimethyl-beta CD (M beta CD), and 2-hydroxypropyl-beta CD (HP beta CD) in aqueous solution with ethanol (EtOH) as a co-solvent. The MD simulation results revealed that EtOH as the co-solvent and the type of cyclodextrin affected the inclusion complex formation. From this study, UC781/M beta CD provided the most stable inclusion complex. The competition for the cavity of beta CD between UC781 and EtOH and the ensuing occupation of beta CD cavities by EtOH resulted in a weaker interaction between beta CD and UC781. In HP beta CD, a supramolecular complex of UC781-HP beta CD-EtOH was formed. The EtOH could easily fill the residual void space of the interior of unoccupied HP beta CD due to the movement of UC781. In M beta CD, the strong hydrogen bond interactions between the UC781 amide group and the secondary hydroxyl groups of M beta CD significantly stabilized the inclusion complex in the presence of EtOH.