Theoretical insights into structural and thermodynamical properties of dentatin/clausarin complexes with β-cyclodextrin derivatives

This study applied computational approached to evaluate β-cyclodextrin (βCD), 2-hydroxypropyl-β-cyclodextrin (HPβCD), and 2,6-dimethyl-β-cyclodextrin (DMβCD) as potential carriers for clausarin (CLA) and dentatin (DEN), coumarin derivatives isolated from the root bark of Clausena excavata. The inclusion behavior and stability of the resulting host-guest complexes were investigated at the molecular level. Molecular docking identified two favorable binding orientations, with either the pyran or pyrone ring of the guests directed toward the primary rim of the CD cavity. Subsequent molecular dynamics simulations confirmed the stability of these complexes, which were mainly stabilized by hydrophobic interactions along with hydrogen bonds at the rim. The MM/PBSA binding free energy calculations showed that HPβCD exhibited the most favorable binding affinity toward both compounds compared to βCD and DMβCD. This trend was further supported by CD-assisted extraction experiments, where HPβCD consistently provided higher extraction efficiency for both CLA and DEN than the native βCD. Taken together, the findings suggest that HPβCD could be a promising carrier among the studied CDs and provide molecular-level insight into CD-coumarin interactions relevant to the development of delivery systems for poorly water-soluble bioactive compounds.