In silico elucidation of the inclusion phenomenon and permeation behavior of a zidovudine–cyclodextrin complex via static lattice atomistic simulation

Abstract

This study explored the molecular arrangement of the drug molecule zidovudine (AZT) within an inclusion complex of β-cyclodextrin (βCD). The intrinsic mechanistic profiling of the AZT–βCD inclusion complex was investigated using molecular modeling and structurally designed docking studies via molecular mechanics Force-Field simulations. The energetically and geometrically optimized molecular conformations revealed that the AZT molecule was preferentially oriented toward the primary rim of the βCD cavity with the azido group positioned within the cyclodextrin ring. In the second phase of this study, the mechanism of AZT permeability across the transmucosal membrane after inclusion into βCD was elucidated via interaction between βCD and the transmucosal lipid, glycosylceramide (GLC). Interestingly, βCD formed H-bonds with the lipid head groups of GLC via the secondary rim. A systematic merge of these findings elucidated a novel “tunnel model” designated to the trimolecular complex: AZT-1°ring–βCD-2°ring–GLC. The energetic parameters, grid surface area, molecular volume, surface-to-volume-ratio, Log-P, refractivity, and polarizability were computed for the molecular complexes. Computationally, the Molecular Mechanics Assisted Model Building and Energy Refinements (AMBER) algorithm was used to develop a molecular mechanics energy relationship (MMER). The MMER elucidated the role of destabilized bond stretching, angle modification and torsional strain in ionic stabilization of the geometrical complexes through hydrophobic H-bonding and electrostatic interactions. These results provided a novel bonding and non-bonding correlation for the formation and performance of βCD in terms of its role in the prospective permeation modification of the AZT molecule through the transmucosal membrane with an optimum hydrophilic–lipophilic-permeation balance.