Title
Theoretical elucidation of the zoledronic acid–β-cyclodextrin inclusion complex: a multi-level analysis using docking, NCI, QTAIM, NMR, NBO, and TD-DFT methods
Authors
WAHIBA BOUNEB, ABDELAZIZ BOUHADIBA, AMINA BENAISSA, NOURA NAILI, MOHAMED RAHIM, YOUGHOURTA BELHOCINE and HASSINA CHEKROUD

Received October 18, 2025
Published Volume 60 Issue 3-4 March-April
Keywords zoledronic acid, β-cyclodextrin, inclusion complex, DFT, non-covalent interactions

Abstract
This study examines the inclusion complexation of zoledronic acid (ZA) with β-cyclodextrin (β-CD) using advanced computational approaches. Density Functional Theory (DFT) calculations with Grimme’s D3 dispersion correction were employed to investigate the molecular structure, stability, non-covalent interactions, and thermodynamic properties of the complex in both gas phase and aqueous solution. The results demonstrate that the inclusion of ZA into the β-CD cavity is thermodynamically favorable, with the most stable configuration identified as configuration A, in which the imidazole moiety of ZA enters through the wider rim of the β-CD. Although solvation in water slightly decreases the overall stability of the complex, it does not significantly hinder its favorable formation. Non-covalent interactions, including hydrogen bonding and van der Waals forces, were analyzed using Natural Bond Orbital (NBO) analysis and the Quantum Theory of Atoms in Molecules (QTAIM). The findings highlight the crucial role of electrostatic interactions in stabilizing the complex, especially in the aqueous phase. Furthermore, NCI-RDG and IGM analyses were conducted to investigate van der Waals contacts, hydrogen bonding, and steric repulsion. Time-Dependent DFT (TD-DFT) calculations were also performed to simulate visible absorption spectra. Nuclear Magnetic Resonance (NMR) chemical shift calculations were carried out to compare theoretical predictions with experimental data, providing additional support for the encapsulation mechanism. Monte Carlo (MC) simulations were used to explore the conformational flexibility and dynamic behavior of the ZA@β-CD complex. These theoretical insights contribute to a deeper understanding of ZA@βCD inclusion complexes and support the design of pharmaceutical formulations aimed at enhancing drug solubility and bioavailability.