Predicting enantiomer migration order of levobunolol via sequential computational modeling

CONTEXT: A detailed molecular-level rationale for the enantioseparation of the β-blocker levobunolol (BUN) by substituted β-cyclodextrins (β-CDs) is presented through high-level computational modeling. The calculations consistently reveal that the therapeutically active (+)-[S]-BUN enantiomer forms more stable inclusion complexes than the (-)-[R]-enantiomer with both carboxymethyl-β-CD (CM-β-CD) and sulfated-β-CD (SF-β-CD) selectors. Non-covalent interaction (NCI) reveals that the superior stability of the S-enantiomer arises from a more continuous dispersive interaction envelope and a more compact network of electrostatic and hydrogen bonds. For the most effective selector, SF-β-CD, the complexation Gibbs free energy (ΔG) in an aqueous medium is -29.5 kcal/mol for (+)-[S]-BUN versus -17.1 kcal/mol for (-)-[R]-BUN. This results in a large free energy difference (ΔΔG) of 12.4 kcal/mol, indicating exceptional enantioselectivity. The NCI isosurfaces also confirm that the S-isomer achieves optimal stereoelectronic complementarity with the host's sulfate and hydroxyl groups, showing lower steric penalties than the R-isomer. These findings provide a robust prediction of a longer electrophoretic migration time for the (+)-[S]-enantiomer and validate SF-β-CD as a highly efficient chiral selector for BUN, underscoring the power of in silico methods to elucidate complex chiral recognition mechanisms. METHODS: Semiempirical geometry, frequency, non-covalent, 2nd version, eXtended Tight Binding (GFN2-xTB) and Density Functional Theory (DFT) (ωB97X-D3/6-31G(d,p) and ωB97X-D3/6-311 + G(d,p)) methods were employed in both gas and aqueous phases. NCI analysis was also performed. All DFT and semiempirical calculations were carried out using the ORCA 5.0 software package. The NCI analysis was carried out using the Multiwfn program.