Refining the Trapping of Therapeutic Agent Silybin A in Functionalized β- and γ-Cyclodextrin Cavitands for Improved Supramolecular Complexation

Silybin A (Slym), the principal bioactive constituent of silymarin, exhibits significant therapeutic potential but suffers from poor bioavailability due to its low aqueous solubility. This study addresses this by employing cyclodextrins (CDs) as cost-effective solubilizers to enhance Slym’s solubility through the formation of stable supramolecular complexes. Our findings indicate that while β-CD and γ-CD have suitable cavity sizes for Slym, their derivatives 6-O-alpha-d-Glucosyl-β-CD (G-β-CD), Heptakis-O-(4-sulfobutyl)-β-CD (SBE-β-CD), and Hydroxypropyl-γ-CD (HP-γ-CD) exhibit superior binding affinity. The binding free energy results from the MM/PBSA analysis indicated that derivatives of β-CD and γ-CD exhibit superior encapsulation efficiency for Slym compared to the unsubstituted CD forms by performing 1 μs MD simulations. Detailed mechanistic insights of these were obtained through 5 μs MD simulations and triplicate analysis, confirming the stability of these complexes over extended durations, attributed to numerous nonbonded interactions. Furthermore, full DFT calculations with M06-2X/6-31g(d) model chemistry revealed that the SBE-β-CD/Slym complex showed the most favorable complexation energy −303.82 kJ/mol than G-β-CD/Slym (−224.82 kJ/mol) and HP-γ-CD/Slym (−246.75 kJ/mol). The QM-derived IR spectrum of the SBE-β-CD/Slym complex was compared with experimental data, and nonbonded interactions between CDs and Slym were analyzed using IGMH analysis. The conformational entry of Slym into CDs was also analyzed, highlighting the potential of SBE-β-CD as an effective carrier for enhancing the solubility and pharmaceutical efficacy of Slym.