Predicting enantiomer migration order of levobunolol via sequential computational modeling

Area of Science:

• Computational Chemistry
• Chiral Separations
• Molecular Modeling

Background:

• Levobunolol (BUN) is a beta-blocker whose enantiomers exhibit different therapeutic activities.
• Substituted beta-cyclodextrins (β-CDs) are used for chiral separations.
• Understanding the molecular basis of enantioseparation is crucial for drug development.

Purpose of the Study:

• To elucidate the molecular-level mechanism of levobunolol (BUN) enantioseparation by substituted beta-cyclodextrins (β-CDs).
• To computationally model and predict the enantioselectivity of carboxymethyl-β-CD (CM-β-CD) and sulfated-β-CD (SF-β-CD) for BUN.
• To validate the efficiency of SF-β-CD as a chiral selector for BUN.

Main Methods:

• High-level computational modeling, including semiempirical GFN2-xTB and Density Functional Theory (DFT) methods.
• Non-covalent interaction (NCI) analysis to investigate intermolecular forces.
• Calculations performed in both gas and aqueous phases using ORCA 5.0 and Multiwfn software.

Main Results:

• The therapeutically active (+)-[S]-BUN enantiomer forms significantly more stable inclusion complexes with both CM-β-CD and SF-β-CD compared to the (-)-[R]-enantiomer.
• SF-β-CD demonstrates exceptional enantioselectivity, with a complexation Gibbs free energy difference (ΔΔG) of 12.4 kcal/mol.
• NCI analysis reveals that the S-enantiomer's superior stability is due to more favorable dispersive, electrostatic, and hydrogen bonding interactions, with lower steric penalties.

Conclusions:

• Sulfated-β-CD (SF-β-CD) is a highly efficient chiral selector for the enantioseparation of levobunolol (BUN).
• The computational model accurately predicts the enantioselective binding and longer electrophoretic migration time of the (+)-[S]-BUN enantiomer.
• In silico methods provide valuable insights into complex chiral recognition mechanisms, aiding in the design of separation processes.