Quantum Chemistry Based Simulation of Enantioseparation on Cyclodextrin- and Polysaccharide-Based Chiral Stationary...

We assess the capability of modern quantum chemical methods to simulate enantioseparation on chiral stationary phases (CSPs) in high-performance liquid chromatography (HPLC) by comparing calculated and experimental elution orders (EEOs). Compared to previous studies, this work utilizes more accurate state-of-the-art density functional theory (DFT) methods combined with automated computational workflows. The proposed approach employs molecular docking, conformer sampling, and DFT refinement for final ensemble-based association free energy calculations of two diastereomeric complexes. Ten drug-type molecules were considered on two common CSPs for which various molecular models were investigated. Although the association free energies of the strongest binding motifs were rather system-dependen t ranging from about -9 to 29 kcal/mol, the differences between the two enantiomers were always only a few kcal/mol, sometimes even below 1 kcal/mol. Despite these small differences, correct determination of EEOs for all tested cyclodextrin-based CSP systems was achieved. Even for more flexible polysaccharide-based CSPs, the workflow yielded correct EEO results in 90 $\%$ of the tested cases, provided that a sufficiently large cut-out of the CSP material consisting of about 150 atoms was considered as a model. Due to the latter constraint, the method remains computationally expensive, requiring further research for improving practical application in, e.g., screening studies.