Evaluating solubility, stability, and inclusion complexation of oxyresveratrol with various β-cyclodextrin derivatives using advanced computational techniques and experimental validation

Oxyresveratrol (OXY), a natural stilbenoid in mulberry fruits, is known for its diverse pharmacological properties. However, its clinical use is hindered by low water solubility and limited bioavailability. In the present study, the inclusion complexes of OXY with beta-cyclodextrin (beta CD) and its three analogs, dimethyl-beta-cyclodextrin (DM beta CD), hydroxypropyl-beta-cyclodextrin (HP beta CD) and sulfobutylether-beta-cyclodextrin (SBE beta CD), were investigated using in silico and in vitro studies. Molecular docking revealed two binding orientations of OXY, namely, 4 ',6 '-dihydroxyphenyl (A-form) and 5,7-benzenediol ring (B-form). Molecular Dynamics simulations suggested the formation of inclusion complexes with beta CDs through two distinct orientations, with OXY/SBE beta CD exhibiting maximum atom contacts and the lowest solvent-exposed area in the hydrophobic cavity. These results corresponded well with the highest binding affinity observed in OXY/SBE beta CD when assessed using the MM/GBSA method. Beyond traditional simulation methods, Ligand-binding Parallel Cascade Selection Molecular Dynamics method was employed to investigate how the drug enters and accommodates within the hydrophobic cavity. The in silico results aligned with stability constants: SBE beta CD (2060 M-1), HP beta CD (1860 M-1), DM beta CD (1700 M-1), and beta CD (1420 M-1). All complexes exhibited a 1:1 binding mode (AL type), with SBE beta CD enhancing OXY solubility (25-fold). SEM micrographs, DSC thermograms, FT-IR and 1H NMR spectra confirm the inclusion complex formation, revealing novel surface morphologies, distinctive thermal behaviors, and new peaks. Notably, the inhibitory impact on the proliferation of breast cancer cell lines, MCF-7, exhibited by inclusion complexes particularly OXY/DM beta CD, OXY/HP beta CD, and OXY/SBE beta CD were markedly superior compared to that of OXY alone.