Inclusion Complexes of Naringenin in Dimethylated and Permethylated β-Cyclodextrins: Crystal Structures and Molecular Dynamics Studies

Abstract

The crystal structures of the inclusion complexes of naringenin in dimethylated and permethylated β-cyclodextrin (DM-β-CD and TM-β-CD) were determined and extensively analyzed. Naringenin is found with its 4-hydroxyphenyl residue fully immersed in the DM-β-CD cavity and its chromone group protruding from the narrow rim of the open-cone shaped host. The naringenin/DM-β-CD complex units are packed in a ‘herring bone’ fashion. In the case of naringenin/TM-β-CD, the complex units are arranged in a cage-type mode, the guest naringenin is partially encapsulated in the cavity of the closed-cone shaped host, with its chromone group laying equatorially and its 4-hydroxyphenyl protruding extensively from the wide rim of the host. Furthermore, the crystallographically-determined coordinates of both complexes were employed for Molecular Dynaimics simulations in explicit water solvent and in the absence of crystal contacts. The trajectories showed that naringenin rapidly penetrates the open narrow rim of DM-β-CD but not the closed narrow rim of TM-β-CD. Thus, in the latter case, the chromone group of naringenin is accommodated shallowly in the wide rim of the host, tethered via hydrogen bonds to the secondary methoxy groups of the host. Finally, a significantly higher binding affinity for naringenin in DM-β-CD than TM-β-CD was estimated by Molecular Mechanics/Generalized Born Surface Area calculations.