Explanation of the Formation of Complexes between Representatives of Oxazolidinones and HDAS-β-CD Using Molecular Modeling as a Complementary Technique to cEKC and NMR

Abstract

Molecular modeling (MM) results for tedizolid and radezolid with heptakis-(2,3-diacetyl-6-sulfo)-β-cyclodextrin (HDAS-β-CD) are presented and compared with the results previously obtained for linezolid and sutezolid. The mechanism of interaction of chiral oxazolidinone ligands belonging to a new class of antibacterial agents, such as linezolid, tedizolid, radezolid, and sutezolid, with HDAS-β-CD based on capillary electrokinetic chromatography (cEKC), nuclear magnetic resonance (NMR) spectroscopy, and MM methods was described. Principles of chiral separation of oxazolidinone analogues using charged single isomer derivatives of cyclodextrin by the cEKC method were presented, including the selection of the optimal chiral selector and separation conditions, complex stoichiometry, and binding constants, which provided a comprehensive basis for MM studies. In turn, NMR provided, where possible, direct information on the geometry of the inclusion complexes and also provided the necessary structural information to validate the MM calculations. Consequently, MM contributed to the understanding of the structure of diastereomeric complexes, the thermodynamics of complexation, and the visualization of their structures. The most probable mean geometries of the studied supramolecular complexes and their dynamics (geometry changes over time) were determined by molecular dynamics methods. Oxazolidinone ligands have been shown to complex mainly the inner part of cyclodextrin, while the external binding is less privileged, which is consistent with the conclusions of the NMR studies. Enthalpy values of binding of complexes were calculated using long-term molecular dynamics in explicit water as well as using molecular mechanics, the Poisson–Boltzmann or generalized Born, and surface area continuum solvation (MM/PBSA and MM/GBSA) methods. Computational methods predicted the effect of changes in pH and composition of the solution on the strength and complexation process, and it adapted the conditions selected as optimal during the cEKC study. By changing the dielectric constant in the MM/PBSA and MM/GBSA calculations, the effect of changing the solution to methanol/acetonitrile was investigated. A fairly successful attempt was made to predict the chiral separation of the oxazolidinones using the modified cyclodextrin by computational methods.

Update on chiral recognition mechanisms in separation science

“…On the other hand, a racemic compound was used for the determination of the complex structure by NMR, which did not allow for detecting differences in the structures of the complexes of the individual enantiomers. In a similar manner, molecular modeling including MD simulations was applied as a complementary technique to rationalize the complexation of oxazolidinones such as linezolid or tedizolid by heptakis (2,3‐di‐ O ‐acetyl‐6‐ O ‐sulfo)‐β‐CD [115]. The calculated differences in the strength of the binding of the enantiomers could predict the enantioseparation.…”

Recognition in the Domain of Molecular Chirality: From Noncovalent Interactions to Separation of Enantiomers

“…For instance, the following strategies were used so far to deal with the modelling of S-β-CD and related complexes: (a) the question is neglected, or the CD is considered as a single isomer; , (b) a structure representing one of the possible structures is randomly generated; (c) different isomeric forms are selected and modelled considering an ensemble of isomers; (d) some authors argue that it is not reliable to model mixtures of CDs . The same trend emerged in the modelling studies involving HP- ,− and CM-β-CD. ,− In the last few years, molecular modelling of HDA, , HDAS, ,− HDMS β-CD, and HMDS β-CD has been performed in several cases by comparing the affinity of these substituted CDs and the corresponding native macrocycle toward chiral analytes. In most cases, the modelling evidenced that substitution at the rims of CDs may enhance the interaction ability of the host and favor the differentiation between diastereomeric complexes through steric repulsion, whereas in some cases the binding modes of enantiomers with native CDs tend to be similar because of the poor flexibility of the host, which limits its discrimination capability.…”