Cucurbit[7]uril complexes with gabapentin: Effect on lactamization

[Display omitted] •Complexes of gabapentin and its lactam form with cucurbit[7]uril in aqueous solution were investigated.•Binding free energies of the complexes were estimated using experimental and computational methods.•Lactamization of gabapentin in the free and bound states was studied experimentally and theoretically.•Structures of the complexes and their dynamics were studied using molecular dynamics simulations. Spectroscopic and computational techniques have been used to study the complexation of gabapentin (GAB) and its lactam form (LAC) with cucurbit[7]uril (CB7) in aqueous solution. 1H NMR and fluorescence displacement titrations demonstrated that CB7 forms 1:1 complexes with GAB and LAC, binding preferentially to LAC (ΔΔG ∼ -4 kcal.mol−1). Furthermore, 1H NMR spectra recorded over a period of two weeks revealed that the rate of GAB lactamization increased when it was encapsulated within the cavity of CB7. This is a direct result of the lower activation free energy of the lactamization process within the cavity of CB7, as computed by quantum-chemical calculations. Molecular dynamics simulations revealed the encapsulation of the cyclohexyl moiety inside the host cavity, while the NH3+ in GAB and NH in LAC interacting with the CB7 portal, in agreement with the NMR results. MM-PBSA results showed that van der Waals interactions provided major favorable contributions to the binding free energies of both guest molecules while the electrostatic contribution was significant only for GAB. MM-PBSA estimates of the binding free energies failed to reproduce the observed preferential affinity of CB7 toward LAC, while thermodynamics integration and density functional theory calculations exhibited much better agreement.