Encapsulation of fluoxetine by cucurbit[7]uril: A computational and experimental study

Fluoxetine (FLX), a selective serotonin reuptake inhibitor, is widely prescribed for the treatment of depression and obsessive-compulsive disorders. However, the administration of FLX can lead to side effects, which may be mitigated by encapsulating the drug within a macrocyclic host. In this study, we explored the complexation of FLX with cucurbit[7]uril (CB7) using 19 F and 1 H NMR spectroscopy, fluorescence displacement titrations, and molecular dynamics (MD) simulations. Our fluorescence results indicate that CB7 forms a 1:1 complex with FLX, with a binding constant of 1.7 x 103 M-1. Additionally, NMR data suggest that the (trifluoromethyl) phenyl moiety of FLX is encapsulated within the CB7 cavity. Molecular dynamics simulations revealed two binding modes for FLX with CB7: one involving the inclusion of the (trifluoromethyl) phenyl moiety and the other involving the phenyl moiety within the CB7 cavity. In both modes, the protonated amine group of FLX interacted with the CB7 portal. Binding free energy calculations using the MM-PBSA method suggested a preference for the inclusion of the phenyl moiety, which contrasts the NMR findings. The interactions between the host and guest were primarily driven by electrostatic forces, with van der Waals interactions playing a lesser, but still favorable, role. In contrast, DFT calculations produced similar binding free energy estimates for the two modes.