Enantioseparation, quantification, molecular docking and molecular dynamics study of five β-adrenergic blockers on Lux-Cellulose-2 column

Abstract

Enantioseparation of five β-adrenergic blockers was studied using two mobile phases on a cellulose tris(3‐chloro‐4‐methylphenylcarbamate) (Lux-Cellulose-2) chiral column in normal phase mode. The first mobile phase composed of n-hexane: ethanol: diethylamine 60: 40: 0.1 by volume has successfully resolved the chromatographic peaks of three pairs of β-adrenergic blockers namely, bisoprolol, carvedilol and atenolol. A mixture of n-hexane: ethanol: diethyl amine 75: 25: 0.1 by volume was used as the second mobile phase to separate the four pairs of enantiomers, metoprolol, carvedilol, nebivolol and atenolol with high resolution values. The mobile phases were pumped at a flow rate 1 mL/min with column temperature 25 °C using a UV detector at 230 nm. Molecular docking simulations of the five pairs of enantiomers was carried out in the cavities of the chiral stationary phase to gain a better understanding of the interaction between analyte enantiomers and chiral stationary phase and to better understand the mechanism of chiral recognition. According to the results, hydrogen bond interactions and π-π- interactions were the main types of interaction involved in the chiral recognition. Molecular dynamics simulation was performed to investigate the solvent effect on the interaction of the five pair of enantiomers in the chiral stationary phase cavity under dynamic conditions.

Molecular Dynamics Simulations of Amylose- and Cellulose-Based Selectors and Related Enantioseparations in Liquid Phase Chromatography

“…On the contrary, models optimized with MD for chlorinated polysaccharide-based selectors are practically missing except for a recent model reported for cellulose tris(3chloro-4-methylphenylcarbamate) (CCMPC) by Aboul-Enein et al [74]. Unfortunately, in this study, details about the construction of the initial structure of the virtual polymer were missing.…”

“…By using a modified version of mod. 14 containing 20-mer ADMPC strands and a diverse combination of force field/software (GROMOS54A7/LAMMPS [74]), Ciriaco et al explored the molecular mechanisms underlying the enantioseparation of chiral compounds 38-41 in a 100 ns MD carried out in the vacuum, and with MeOH or n-hexane/MeOH 90:10 as explicit solvents, in accordance with chromatographic analysis [67]. The authors found consistent differences between each enantiomer throughout the trajectories, revealing that HB, steric hindrance, and π-π interactions played major roles in enantiomeric separation.…”

“…Very recently, Aboul-Enein et al carried out 500 ps MD simulations to investigate the solvent effect on the interaction of the chiral β-adrenergic blockers 42-46 with CCMPC [74], considering EtOH as the explicit solvent. However, the MD study presents several flaws, in particular, (a) details on the construction of the virtual polymers are missing, and (b) the virtual solvent (EtOH) included in the MD system was not consistent with the mobile phases (n-hexane-based mixtures) used experimentally.…”

Update on chiral recognition mechanisms in separation science

“…In contrast to an earlier summary [17], an increasing number of publications studied cellulose-based selectors [66,[71][72][73][74][75][76] compared to amylose-based selectors [69,70,[77][78][79]. Most often the enantioseparations were achieved under normal-phase conditions [70][71][72][73][74][76][77][78][79], but reversedphase elution [75,78] and polar organic mode [66,69] were also applied. The group of Carotti combined circular dichroism with molecular modeling to establish the enantiomer elution order of two tetracyclic quinoline derivatives composed of four stereoisomers when pure enantiomeric standards are not available [71].…”

“…Recent studies combining HPLC enantioseparations on polysaccharide CSPs with computational modeling techniques have been summarized in Table 1. In contrast to an earlier summary [17], an increasing number of publications studied cellulose-based selectors [66,[71][72][73][74][75][76] compared to amylose-based selectors [69,70,[77][78][79]. Most often the enantioseparations were achieved under normal-phase conditions [70][71][72][73][74][76][77][78][79], but reversedphase elution [75,78] and polar organic mode [66,69] were also applied.…”