Chlorpropamide-cyclodextrin inclusion complexes, theoretical basis of stability

Abstract

A study of the stability of inclusion complexes of chlorpropamide and α, β, γ, and HP-β cyclodextrin, has been carried out using molecular dynamics simulations. The contribution of weak interactions to the stability of the complexes through DFT has been analyzed. The conventional molecular dynamics analysis suggests stable complexes for the inclusion of chlorpropamide. As expected, the complex stabilization is driven by hydrophobic interactions between cyclodextrin and chlorpropamide aromatic ring; similar mobility of chlorpropamide in the cyclodextrin cavities was observed. Molecular dynamics results indicate that intermolecular hydrogen bonds appeared between 17.70 and 22.52 % of the simulation time; consequently, the crucial complex stabilizing interactions encompass more than just hydrogen bonds, revealing a more intricate network of stabilizing forces at play. For the first time, based on quantum chemistry, a correlation between the electron density contributions to weak interactions and the glucopyranose units in each CD is presented. The most relevant stabilizing interactions are of the van der Waals type, followed by small contributions from hydrogen bonds. Non-covalent interactions are more intense in the chlorpropamide/HP-β cyclodextrin complex than in other systems. The inclusion complexes formed with β-type cyclodextrins are the most stable (due to the number and intensity of the contributions), in agreement with the molecular dynamics simulation results. In addition, MMPBSA and QM energies predict CPD/αCD as unstable and least stable complex, respectively. These results highlight the importance of β-type cyclodextrins in the formation of creating reliable inclusion complexes, which could be potentially applied to molecular encapsulation and drug delivery systems.