Energetic and Non-covalent Interaction Insights in Host–Guest Chemistry: A Case Study of Metronidazole-β-Cyclodextrin Complex

Abstract

Metronidazole (MNZ) displays notable biological activity; however, it is encumbered by suboptimal physicochemical and pharmacokinetic properties. To address these limitations, researchers have explored the formation of inclusion complexes with cyclodextrins. The present study aims to elucidate the inclusion mechanism of MNZ and β-cyclodextrin (β-CD) in a 1:1 stoichiometry, spanning from electronic structure to non-covalent interactions. Two orientations of MNZ were evaluated: in orientation A, MNZ enters through the wide rim; in orientation B, through the narrow rim. Semi-empirical and density functional theory (DFT) calculations, including dispersion-correction DFT (DFT–D3), were performed in gas and water phases using PW6B95, PW6B95–D3, and B3LYP functionals in conjunction with the 6-31G(d) basis set. The study systematically compared the performance of these methods, with a particular focus on the impact of dispersion correction on the accuracy and reliability of the results. The findings obtained from this study indicate that orientation A is more favorable than B. In both orientations, MNZ is fully encapsulated in the β-CD cavity. The Gauge-Including Atomic Orbital (GIAO) method was employed to calculate the shifts of the proton nuclear magnetic resonance (¹H NMR), which aligned well with the experimental data. To further analyze host–guest interactions, advanced computational tools: AIM, NBO, NCI–RDG, and IGM were utilized. These analyses revealed that the stability of the MNZ@β-CD inclusion complex is driven by hydrogen bonding and van der Waals interactions, with dispersion corrections (DFT–D3) playing a critical role in accurately modeling these non-covalent forces. This study provides an exhaustive analysis of the molecular interactions driving the formation of MNZ@β-CD complexes, emphasizing the reliability of the PW6B95 and PW6B95–D3 functionals and the necessity of incorporating dispersion corrections for an accurate description of these systems.