Molecular Insights into the Inclusion Complexation of 5,7-Dimethoxyflavone with β‑cyclodextrin Derivatives: A Combined Experimental and Computational Study

5,7-Dimethoxyflavone (5,7-DMF) is a bioactive flavonoid with broad pharmacological potential; however, its poor aqueous solubility limits pharmaceutical development. To address this, we explored the inclusion complexation of 5,7-DMF with β-cyclodextrin (βCD) and its derivatives hydroxypropyl-βCD (HPβCD) and sulfobutylether-βCD (SBEβCD) using an integrated computational and experimental strategy. Molecular docking identified potential binding orientations, which were further evaluated by 500 ns classical MD simulations to examine conformational dynamics and host–guest stability. LB-PaCS MD simulations captured unbiased ligand entry, showing rapid and stable encapsulation primarily through the primary rim (∼80%), with both B-form and C-form complexes, and C-form being more stable. Binding free energy analyses using MM/GBSA and MM/PBSA, supported by QM/MM calculations (ωB97XD/def2-TZVP:HF/6–31G(d)), consistently ranked SBEβCD as the most favorable host. Phase solubility studies further corroborated these findings, showing significantly enhanced solubility for the SBEβCD complex, consistent with the computational predictions. Experimental characterization of the freeze-dried complexes by 1H NMR validated the inclusion of 5,7-DMF within the cyclodextrin cavities. Collectively, this study provides mechanistic insights into the host–guest interaction landscape of 5,7-DMF with CD carriers and supports the rational design of CD-based delivery systems to improve solubility and bioavailability of hydrophobic therapeutics.