Chiral Recognition of Butylone by Methylated β-Cyclodextrin Inclusion Complexes: Molecular Calculations and Two-Level...

The integration of molecular docking and AM1 calculations has elucidated the complexation behavior of butylone enantiomers with methylated β-cyclodextrin derivatives. Our study reveals that butylone can adopt two distinct conformations within the β-cyclodextrin cavity, with one conformation being preferentially stabilized due to its favorable binding energy. This conformation preference is influenced by the methylation at the O2, O3, and O6 positions of β-cyclodextrin, which significantly affects complex stability and solvation properties. Factorial design analysis further highlights the critical role of these methylation sites in modulating the complexation energies. The heptakis(2,6-di-O-methyl)-β-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin exhibit distinct enantioseparation mechanisms for butylone, attributed to variations in hydrogen bonding and cavity interactions. This theoretical investigation not only corroborates experimental findings but also offers a detailed understanding of the molecular mechanisms underlying chiral recognition of butylone by methylated β-cyclodextrins. These insights facilitate the rational design of novel chiral selectors for analytical and separation applications. Future research can build upon these findings to explore similar interactions with other chiral synthetic cathinones, potentially advancing predictive capabilities and reducing experimental costs in chiral separation technology development.