Combination of capillary electrophoresis and molecular modeling to study the enantiomer affinity pattern between β-blockers and anionic cyclodextrin derivatives in a methanolic and water background electrolyte.

In order to have deep insights into the mechanisms of enantiomer affinity pattern in both aqueous and non-aqueous systems, an approach combining capillary electrophoresis and molecular modeling was undertaken. A chiral β-blocker, acebutolol, was enantioseparated in aqueous CE and non-aqueous CE using two anionic β-cyclodextrin derivatives. The enantiomer affinity pattern of acebutolol was found to be opposite when an aqueous background electrolyte was replaced with non-aqueous background electrolyte in the presence of heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin but remained the same in the presence of heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin. Molecular docking of acebutolol into two β-cyclodextrin derivatives indicated two distinct binding modes called 'up' and 'down' conformations. After structure optimization by molecular dynamics and energy minimization, both enantiomers of acebutolol were prefered to the 'up' conformation with heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin while 'down' conformation with heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin. The further calculation of the complex energy with solvent effect indicated that heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin had higher affinity to S-acebutolol than R-acebutolol in non-aqueous CE while it showed better binding to R-acebutolol in aqueous CE. However, the heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin bound better to R-acebutolol in both aqueous and non-aqueous CE, implying the binding mode played a more important role in chiral separation of heptakis(2,3-di-O-methyl-6-sulfo)-β-cyclodextrin while the solvent effect had prevailing impact on heptakis(2,3-di-O-acetyl-6-sulfo)-β-cyclodextrin. This article is protected by copyright. All rights reserved.