Influence of host cavity dimensions on the stability of cyclodextrin-based urease inhibitor formulations: a theoretical study

Abstract The design of efficient delivery systems for urease inhibitors is a critical challenge in mitigating nitrogen loss in agriculture. In this work, we investigated the molecular recognition and inclusion of phosphoramidate (PHOS) derivatives within the cavities of α -, β -, and γ -cyclodextrins (CDs). A hierarchical computational strategy was employed using the ORCA 5.0 package, starting with geometry optimizations at the semiempirical GFN2-xTB level, followed by refined electronic energy calculations utilizing Density Functional Theory (DFT) with the range-separated hybrid functional ωB97X-D3 and the 6-31G(d,p) basis set. Solvation effects in water were accounted for using the Solvation Model based on Density (SMD), and the nature of host-guest stabilization was characterized via Non-Covalent Interaction (NCI) index analysis. We demonstrate that host cavity dimensions are the primary determinant of complex stability. Our results reveal that β -CD provides the optimal hydrophobic environment, exhibiting superior host-guest complementarity for PHOS compared to its α- and γ-congeners. This “optimal steric complementarity” fit maximizes stabilizing non-covalent interactions, yielding a denser network of hydrogen bonds and enhanced London dispersion forces within the β -CD framework. These findings provide a definitive molecular basis for the preference for β -CD in both gas and aqueous phases, offering a predictive blueprint for the rational design of advanced, controlled-release nitrogenous fertilizer formulations.