Different Drug Mobilities in Hydrophobic Cavities of Host–Guest Complexes between β-Cyclodextrin and 5-Fluorouracil at Different Stoichiometries: A Molecular Dynamics Study in Water

Cyclodextrins (CDs) are cyclic oligosaccharides able to form noncovalent water-soluble complexes useful in many different applications for the solubilization, delivery, and greater bioavailability of hydrophobic drugs. The complexation of 5-fluorouracil (5-FU) with natural or synthetic cyclodextrins permits the solubilization of this poorly soluble anticancer drug. In this theoretical work, the complexes between beta-CD and 5-FU are investigated using molecular mechanics (MM) and molecular dynamics (MD) simulations in water. The inclusion complexes are formed thanks to the favorable intermolecular interactions between beta-CD and 5-FU. Both 1:1 and 1:2 beta-CD/5-FU stoichiometries are investigated, providing insight into their interaction geometries and stability over time in water. In the 1:2 beta-CD/5-FU complexes, the intermolecular interactions affect the drug's mobility, suggesting a two-step release mechanism: a fast release for the more exposed and hydrated drug molecule, with greater freedom of movement near the beta-CD rims, and a slow one for the less-hydrated and well-encapsulated and confined drug. MD simulations study the intermolecular interactions between drugs and specific carriers at the atomistic level, suggesting a possible release mechanism and highlighting the role of the impact of the drug concentration on the kinetics process in water. A comparison with experimental data in the literature provides further insights.