High field NMR techniques, molecular modelling and molecular dynamics simulations in the study of the inclusion complex of the cognition activator (±)-1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid (CI-933) with β-cyclodextrin

The formation of the inclusion complex of β-cyclodextrin with the new cognition activator (±)-1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid (CI-933) and the chiral discrimination capability of the macrocyclic host towards the racemic guest were evident from 1H NMR studies. The structure, relative host-guest orientation and binding mode of the complex were studied using the ROESY NMR technique complemented by molecular modelling and molecular dynamics simulations (charmm). All these methods converged towards the structure attained by inserting the guest, the aromatic ring first, into the hydrophobic cavity of the host from the side of the secondary hydroxyls. Both the R- and S-enantiomers were found deeply inserted into the host, the diastereoisomeric complexes formed featuring different numbers and distribution of intermolecular hydrogen bonds.