The Composition of the Mobile Phase Affects the Dynamic Chiral Recognition of Drug Molecules by the Chiral Stationary Phase

Abstract

More than half of all pharmaceuticals are chiral compounds. Although the enantiomers of chiral compounds have the same chemical structure, they can exhibit marked differences in physiological activity; therefore, it is important to remove the undesirable enantiomer. Chromatographic separation of chiral enantiomers is one of the best available methods to get enantio-pure substances, but the optimization of the experimental conditions can be very time-consuming. One of the most widely used chiral stationary phases, amylose tris(3,5-dimethylphenyl carbamate) (ADMPC), has been extensively investigated using both experimental and computational methods; however, the dynamic nature of the interaction between enantiomers and ADMPC, as well as the solvent effects on the ADMPC-enantiomer interaction, are currently absent from models of the chiral recognition mechanism. Here we use QM/MM and molecular dynamics (MD) simulations to model the enantiomers of flavanone on ADMPC in either methanol or heptane/2-propanol (IPA) (90/10) to elucidate the chiral recognition mechanism from a new dynamic perspective. In atomistic MD simulations, the 12-mer model of ADMPC is found to hold the 4/3 left-handed helical structure in both methanol and heptane/IPA (90/10); however, the ADMPC polymer is found to have a more extended average structure in heptane/IPA (90/10) than in methanol. This results from the differences in the distribution of solvent molecules close to the backbone of ADMPC leads to changes in the distribution of the (φ, ψ) dihedral angles of the glycoside bond (between adjacent monomers) that define the structure of the polymer. Our simulations have shown that the lifetime of hydrogen bonds formed between ADMPC and flavanone enantiomers in the MD simulations are able to reproduce the elution order observed in experiments for both the methanol and the heptane/IPA solvent systems. Furthermore, the ratios of hydrogen-bonding-lifetime-related properties also capture the solvent effects, in that heptane/IPA (90/10) is found to make the separation between the two enantiomers of flavanone less effective than methanol, which agrees with the experimental separation factors of 0.9 versus 0.4 for R/S, respectively.

Noncovalent interactions in high-performance liquid chromatography enantioseparations on polysaccharide-based chiral selectors

“…This observation appears to be in accord with the 12-mer ADMPC structures obtained by Murad and co-workers through MD simulation performed by using pure methanol and the mixture n-heptane/2-propanol 90:10 as explicit solvents (Fig. 10) [104]. The configurations of ADMPC in different solvents had qualitatively the same left-handed helical nature, but their dimensions varied in different solvents.…”

“…Recently, explicit-solvent MD simulations were performed by Murad and co-workers in order to elucidate the chiral recognition mechanism of the enantioseparation of flavanone (23) enantiomers on ADMPC [104]. For this purpose, a 12-mer oligomer was built on the basis of the parametrization reported by Okamoto's group, and methanol or heptane/IPA (90/10) were used as explicit solvents.…”

Recent studies of docking and molecular dynamics simulation for liquid‐phase enantioseparations

“…In Table , a summary of some representative docking and MD studies published in the period 2015‐2018 is reported . Firstly, in polysaccharides modelling, an important issue concerns the preparation of a built polymer which is representative of the ‘real’ polysaccharide derivative.…”

“…Consequently, in polar solvents (DC ≥ 8.58) the S ‐enantiomer·CSP complex appeared more stable than the R ‐enantiomer·CSP complex, according to the experimental EEO of R ‐ S reported for 10 by using PO solvent or NP with an alcohol content ≥ 30%. Murad and co‐workers used QM/MM and MD simulations to model the enantiomers of flavanone 11 on a 12‐mer ADMPC (100 ns of simulation time) . It is worth noting that the hybrid QM/MM approach is not uncommon in this field because it combines the accuracy of QM and speed of MM, allowing for the study of large molecules in solution.…”

Interfacial Thermal Conductivity and Its Anisotropy

“…Molecular dynamics (MD) is an ideal tool for investigating interfacial thermal resistances. Computational and theoretical studies have many advantages over experiments: first, they do not require the actual manufacturing of nano-devices which can be challenging in itself; second, computational studies involve a small fraction of the cost of experiments; additionally, these studies can be carried out at extreme operating conditions, such as high temperature and high pressure; and finally, they offer molecular-level understanding of the phenomena involved [20,21]. Sofos et al [22] reported anisotropy and non-homogeneity of liquid argon flowing through a nanochannel by using non-equilibrium molecular dynamics (NEMD) simulations.…”