Metronidazole (MTZ) exhibits potent biological activity, but it has issues with its physicochemical and pharmacokinetic properties. These issues could be resolved and optimized by forming inclusion complexes with cyclodextrins. This work evaluates the interactions between MNZ and β-CD with 1:1 stoichiometry using various molecular modeling and computational methods. Two orientations of MNZ, A, and B, were considered.

The techniques used include semi-empirical (PM3) and (DFT) calculations in gas and water using PW6B95, PW6B95D3, and B3LYP functional and 6-31G(d) basis sets. The results indicate that orientation A is more favorable than orientation B. In both orientations, metronidazole was completely embedded into the β-CD cavity. The Gauge-Including Atomic Orbital (GIAO) method was used to calculate 1H NMR shifts, which agreed well with experimental results. To better understand the intra-and intermolecular interactions between the host and the guest (β-CD and MNZ), an investigation was carried out using AIM, NBO, (RDG) NCI, and IGM analysis. The investigation confirmed the stability of the inclusion complex β-CD@MNZ due to H-bond and van der Waals interactions.