Unraveling theR-Enantiomer Preference in Mirror-ImageCyclodextrin: An Integrated Multiscale Computational Study

Abstract

Abstract L-β-Cyclodextrin (L-CD), the mirror-image isomer of native β-cyclodextrin, provides a conceptually novel chiral microenvironment for pharmaceutical enantioseparation; however, its full separation potential and recognition mechanism remain largely unexplored, hindering its rational development. Herein, a multiscale computational framework integrating high-throughput molecular docking, molecular dynamics (MD) simulations, and density functional theory (DFT) calculations was developed to elucidate the chiral recognition mechanism of L-CD toward three clinically drugs, namely baclofen (Bacl), naproxen (Nap), and propranolol (Prop). Batch docking of 150 enantiomer pairs reveals that L-CD discriminates approximately 57% of the evaluated species, with a distinct preference for R-enantiomers in the 200–300 Da range. Subsequent MD simulations further demonstrated that R-enantiomer complexes possess enhanced structural stability, tighter cavity adaptation, and more persistent hydrogen bonds. Binding free energy calculations consistently yield stronger binding affinities of L-CD for R-enantiomers across all three drugs, exemplified by R-Bacl/CD (−72.05 kJ/mol) vs. S-Bacl/CD (−67.99 kJ/mol), R-Nap/CD (−67.46 kJ/mol) vs. S-Nap/CD (−66.03 kJ/mol), and R-Prop/CD (−79.51 kJ/mol) vs. S-Prop/CD (−73.59 kJ/mol). Energy decomposition analysis further reveals that reduced steric hindrance and favorable electrostatic interactions contribute to the enhanced stability of R-enantiomer complexes. This multiscale framework provides atomic-level insights into dynamic chiral recognition by L-CD and establishes a robust theoretical foundation for the rational design of next-generation L-CD-based chiral separation materials.