Deciphering the multi-state binding and dissociation of fenofibrate with β-cyclodextrin and its derivatives: Insights from phase solubility analysis and molecular modeling

The present study focuses on elucidating the multi-state binding and dissociation interaction of fenofibrate (FNB) with β-cyclodextrin and its derivatives hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), with a specific emphasis on the correlation between phase solubility analysis and molecular modeling. The dynamic complexation, conformational stability, configuration transition, and binding energy (ΔEbinding) were investigated based on molecular dynamics (MD) simulations. Subsequently, the quantum mechanical calculations were performed to strengthen the MD results. The dissociation of FNB from both rims of the three cyclodextrins (CDs) was examined using umbrella sampling simulations. The FNB molecule was found to bind to CD in a 1:1 stoichiometry with spontaneous and thermodynamic favorability. The binding ability of FNB with three CDs was arranged in the following sequence: SBE-β-CD > HP-β-CD > β-CD. Moreover, the binding conformations in parallel showed a lower ΔEbinding than those in an anti-parallel arrangement. The FNB molecule exhibited an equal probability of dissociating from the primary and secondary cavity orientations of β-CD. In contrast, for HP-β-CD and SBE-β-CD, FNB tended to dissociate from the primary cavity positions. The combination of the phase solubility method with molecular modeling afforded an in-depth and comprehensive understanding of the interactions between FNB and different CDs and has the potential to be generally applicable to the design and optimization of CD carrier materials to enhance the water solubility of poorly soluble compounds. © 2024 Elsevier B.V.