Molecular Modeling Study of Chiral Separation and Recognition Mechanism of β-Adrenergic Antagonists by Capillary Electrophoresis

Abstract

Chiral separations of five β-adrenergic antagonists (propranolol, esmolol, atenolol, metoprolol, and bisoprolol) were studied by capillary electrophoresis using six cyclodextrins (CDs) as the chiral selectors. Carboxymethylated-β-cyclodextrin (CM-β-CD) exhibited a higher enantioselectivity power compared to the other tested CDs. The influences of the concentration of CM-β-CD, buffer pH, buffer concentration, temperature, and applied voltage were investigated. The good chiral separation of five β-adrenergic antagonists was achieved using 50 mM Tris buffer at pH 4.0 containing 8 mM CM-β-CD with an applied voltage of 24 kV at 20 °C. In order to understand possible chiral recognition mechanisms of these racemates with CM-β-CD, host-guest binding procedures of CM-β-CD and these racemates were studied using the molecular docking software Autodock. The binding free energy was calculated using the Autodock semi-empirical binding free energy function. The results showed that the phenyl or naphthyl ring inserted in the hydrophobic cavity of CM-β-CD and the side chain was found to point out of the cyclodextrin rim. Hydrogen bonding between CM-β-CD and these racemates played an important role in the process of enantionseparation and a model of the hydrogen bonding interaction positions was constructed. The difference in hydrogen bonding formed with the –OH next to the chiral center of the analytes may help to increase chiral discrimination and gave rise to a bigger separation factor. In addition, the longer side chain in the hydrophobic phenyl ring of the enantiomer was not beneficial for enantioseparation and the chiral selectivity factor was found to correspond to the difference in binding free energy.

Enantioseparation of chiral pharmaceuticals by vancomycin‐bonded stationary phase and analysis of chiral recognition mechanism

“…29,30 In a molecular mechanics simulation, the primary mechanisms contained H-bonding, van der Waals interaction, steric repulsion, and electrostatic interaction. 29,30 In a molecular mechanics simulation, the primary mechanisms contained H-bonding, van der Waals interaction, steric repulsion, and electrostatic interaction.…”

“…30,32 The molecular three-dimensional structures of chiral pharmaceuticals containing S-and R-isomers were obtained from the Pubchem database (https://pubchem. It should be noticed that there were usually some assumptions in modeling chiral separations of chromatographic techniques using docking method, such as not taking solvation effect, buffer effect and entropy difference into consideration.…”

Recent advances in electrodriven enantioseparations

“…The ammonium group attempts interactions with a sulfate group as well as an oxygen of the acetyl residues which makes this conformation energetically less favorable compared to the complex of the S ‐enantiomer . Differences in the structures of complexes formed between the enantiomers of β‐adrenergic antagonists including propranolol with carboxymethyl‐β‐CD have also been found by docking experiments .…”

Study on the separation of ofloxacin enantiomers by hydroxyl-propyl-β-cyclodextrin as a chiral selector in capillary electrophoresis: a computational approach

“…Semiempirical methods are attracting lots of attention in the simulation of CD-inclusion compounds due to their reasonable accuracy and less computational demands. These studies were directed to unravel the nature of interaction between the host and the guest molecules to help in understanding the mechanism of complexation [4,18,[22][23][24][25][27][28][29][30][31]. These calculations have also been used to investigate the mechanistic characteristics of chiral recognition using supramolecular systems.…”

“…The methods employed include molecular mechanics, molecular dynamics, semiempirical methods and density functional theory calculations [4,[18][19][20][21][22][23][24][25][26]. Semiempirical methods are attracting lots of attention in the simulation of CD-inclusion compounds due to their reasonable accuracy and less computational demands.…”