Abstract

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 −
cyclodextrin ( −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 −cyclodextrin. This complex aims to increase verbenone
solubility while decreasing volatility for maximum activity. The PM3 method was used to
optimize the verbenone*−cyclodextrin complex as a first excess. The guest was oriented
once toward the wide side of the −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 −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
−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 −CD , which is stabilized by van der Waals and hydrogen
interactions.
Djamel Bouchouk,

Information

Item Type:	Journal
Divisions:	» Laboratory of Organic chemistry and interdisciplinary
ePrint ID:	5375
Date Deposited:	2025-04-21
Further Information:	Google Scholar
URI:	https://www.univ-soukahras.dz/en/publication/article/5375

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