Theoretical study on chiral recognition of vinpocetine, ketoconazole, bromuconazole and propiconazole stereoisomers by teicoplanin aglycone chiral selector

Abstract

Chiral separation has been an important issue as stereochemistry significantly influences the biological activity. In some cases, one stereoisomer may show effectiveness in pharmacology activities while the other may appear toxic. Therefore, it is crucial to develop technology for chiral separation. With the aid of computational tools, a better understanding of the interactions between both drug and fungicide stereoisomers with teicoplanin aglycone (TAG) chiral selector can be achieved before the experiment is conducted. To date, no complexation study of vinpocetine (VP), ketoconazole (KTZ), bromuconazole (BMZ) and propiconazole (PPZ) stereoisomers with TAG chiral selector has been reported. In this study, computational tools were used in the complexation study of drug and fungicide stereoisomers with TAG. This study aimed to give a better understanding of intermolecular interactions such as hydrogen bonding, p-p interaction and hydrophobic interaction between stereoisomers and chiral selector which can assist in chiral separation analysis. Docking simulation was used to find the best conformation of stereoisomers with TAG chiral selector followed by quantummechanic calculation representing the second phase of this study at B3LYP/6-31G(d) density functional theory (DFT) level of theory. All the theoretical calculations were performed using GAUSSIAN09 suite. The lower the binding energy, the more stable the interactions of complexes are. The results showed that the stability of inclusion complexes based on binding energy differences obtained from B3LYP/6-31G(d) calculations for VP, KTZ, BMZ and PPZ stereoisomers with TAG chiral selector were in the order of: (3S16R)VP-TAG (|??E|= 0.00 kcal mol-1) > (3R16R)VP-TAG (|??E|= 5.94 kcal mol-1) > (3R16S)VP–TAG (|??E|= 8.27 kcal mol-1) > (3S16S)VP-TAG (|??E|= 10.59 kcal mol-1); (2R4R)KTZ-TAG (|??E|= 0.00 kcal mol-1) > (2R4S)KTZ-TAG (|??E|= 1.43 kcal mol-1) > (2S4R)KTZ–TAG (|??E|= 6.18 kcal mol-1) > (2S4S)KTZ-TAG (|??E|= 10.20 kcal mol-1); (2S4S)BMZ-TAG (|??E|= 0.00 kcal mol-1) > (2S4R)BMZ-TAG (|??E|= 3.07 kcal mol-1) > (2R4S)BMZ-TAG (|??E|= 6.71 kcal mol-1) > (2R4R)BMZ-TAG (|??E|= 10.62 kcal mol-1); (2R4S)PPZ-TAG (|??E|= 0.00 kcal mol-1) > (2S4S)PPZ-TAG (|??E|= 2.66 kcal mol-1) > (2S4R)PPZ-TAG (|??E|= 4.15 kcal mol-1) > (2R4R)PPZ-TAG (|??E|= 5.92 kcal mol-1), respectively. Results of all binding energy differences of the inclusion complexes between these four drug and fungicide stereoisomers (VP, KTZ, BMZ, PPZ) with TAG chiral selector were considered a measurement of the chiral discrimination together with their interactions such as hydrogen bond, p-p interaction and others. All complexation showed that chiral separation can be achieved using TAG chiral selector. It is expected that the final results from the quantum-mechanic calculation will be useful to further explain the chiral separation analysis at experimental level.