Computational Exploitation of Verbenone Encapsulation by β–Cyclodextrin: Revealing Structure, Energies, and Non-covalent Interactions.

Despite having significant pharmaceutical potential, many compounds are avoided by researchers due to their low solubility and high volatility. These characteristics make them difficult to manipulate and incorporate into drug formulations. Cyclodextrins solve this problem by increasing the solubility of bioactive molecules, making them easier to handle and significantly improving bioavailability. These macromolecules have a wide range of applications, including pharmaceuticals, agriculture, cosmetics, and the environment. This paper presents a computational study of an inclusion complex between verbenone and \(\beta -\)cyclodextrin (\(\beta {-}\text {CD}\)) with a 1 : 1 stoichiometry. The objective is to improve understanding of anomalies that were not identified during experiments and explain why verbenone forms a good complex with \(\beta -\)cyclodextrin. This complex aims to increase verbenone solubility while decreasing volatility for maximum activity. The PM3 method was used to optimize the verbenone*\(\beta -\)cyclodextrin complex as a first excess. The guest was oriented once toward the wide side of the \(\beta {-}\text {CD}\) (orientation A) and another toward the narrow side (orientation B), with inclusion simulation using hyperchem 8.0 software. After calculating the complexation energies and determining the optimal complexes, these complexes were re-optimized using density function methods: B3LYP, MN15, and MN15L with a base set 6-31 G(d,p) in gas and aqueous phases. Theoretical calculations were performed with Gaussian16 software, and visualization was carried out using Gaussview 6. According to the optimal 3D structures, the verbenone was fully encapsulated in the \(\beta {-}\text {CD}\) cavity. The complexation energies, HOMO-LUMO orbitals, and reactivity parameters were calculated. Their analysis confirms that the complex at orientation A is more stable and electrophilic than that at orientation B, and the charge is transferred from the host to the guest. Natural binding orbitals (NBO) were also analyzed. The QTAIM, RDG-NCI, and IGM analyses were interpreted to consider the non-covalent interactions that maintain stability between \(\beta {-}\text {CD}\) and verbenone. Data analysis and visualization were performed using Multiwfn and VMD. The chemical shifts of verbenone protons in the free and complex states were calculated and compared to experimental data. The findings show the formation of a complex between verbenone and \(\beta {-}\text {CD}\), which is stabilized by van der Waals and hydrogen interactions.