Stereoselective inclusion mechanism of ketoprofen into β-cyclodextrin: insights from molecular dynamics simulations and free energy calculations

The host–guest inclusion mechanism formed between β-cyclodextrin and those poorly water-soluble drug molecules has important applications in supramolecular chemistry, biology and pharmacy. In this work, the chiral recognition ability of β-cyclodextrin to one of nonsteroidal anti-inflammatory drugs, ketoprofen, has been systematically investigated using molecular dynamics and free energy simulation methods. The R- and S-enantiomers of ketoprofen were explicitly bound within the cyclodextrin cavity in our simulations, respectively. In consistent with experimental observations, tiny structural difference between two isomers could be observed. Calculated absolute binding free energies using adapted biasing force (ABF) method and MM/GBSA approach for both isomers are comparable to experimental values. Significant binding fluctuations along the MD trajectory have been observed. The free energy profiles calculated using two different approaches reveal that the ketoprofen prefers binding in the cavity with the carboxylate group facing the wider edge of β-cyclodextrin. Similar free energy profiles for two enantiomers obtained using ABF calculations indicate that it is very hard to separate and identify the chiral conjugates within the framework of the natural β-cyclodextrin.