Exploring cyclodextrin-glabridin inclusion complexes: Insights into enhanced pharmaceutical formulations

Glabridin (GbD), a plant-derived bioactive molecule, exhibits diverse biological activities as documented in the literature. However, its low aqueous solubility limits its clinical utility and bioavailability. This study extensively screened β-cyclodextrin (β-CD), γ-CD, and their derivatives to identify the optimal CD for GbD encapsulation to enhance its bioavailability. Molecular dynamics simulations were performed on all docked inclusion complexes (ICs), with selection based on binding energy scores derived via the MM/PBSA method. The selected complexes, γ-CD/GbD and Octakis(6-O-sulfo)-γ-CD/GbD-1, underwent robust umbrella sampling simulations and quantum mechanics calculations using the DFT method (wB97X-D/6-311 + G(d,p)) to determine their thermodynamics. Additionally, MD simulations of the most stable ICs were conducted over a temperature range of 35 °C to 75 °C to assess temperature-dependent structural stability. The analysis revealed higher stability for the Octakis(6-O-sulfo)-γ-CD/GbD-1 complex, attributed to its more favorable Gibbs free energy (−349.92 kJ/mol) compared to γ-CD/GbD (−141.18 kJ/mol). The primary focus of the research was to maximize non-covalent interactions by selecting the appropriate CD form, with Octakis(6-O-sulfo)-γ-CD exhibiting the highest number of non-covalent interactions as elucidated by the IGMH method. Consequently, the Octakis(6-O-sulfo)-γ-CD/GbD-1 IC in 1:1 stoichiometry presents a promising strategy for the future clinical application of GbD. © 2024 Elsevier B.V.