Substituent Size and Interaction Type Shape Sulfonylurea–β-Cyclodextrin Binding Modes

Sulfonylureas are hypoglycemic agents used in type 2 diabetes mellitus, although their low water solubility implies high therapeutic doses. Inclusion complexes with β-cyclodextrin (β-CD), a cyclic oligosaccharide featuring a hydrophobic interior and hydrophilic exterior, offer a supramolecular polymer capable of encapsulating drugs, improving solubility and stability. We explore how substituent size and interaction type influence the stability of β-CD complexes with <i>p</i>-toluenesulfonylurea, tolbutamide, and tolazamide. Using molecular dynamics simulations, clustering analysis, and quantum chemistry calculations at the M06-2X-D3/ACP-6-31G(d) + SMD level of theory, we identified the most stable binding modes. Boltzmann populations of complexes revealed a single dominant conformation for <i>p</i>-toluenesulfonylurea (∼97%), two major coexisting conformations for tolbutamide (75/25%), and two near-equal conformations for tolazamide (56/43%). Predominant conformations adopted by guest molecules are in line with experimental reports. Binding free energies, determined via molecular mechanics Poisson-Boltzmann surface area analysis, for <i>p</i>-toluensulfonylurea, tolbutamide and tolazamide in β-CD inclusion complexes, averaged -10.75, -13.42, and -12.84 kcal mol^-1, respectively. Interaction energies increased with bulkier substituents, though this was partially offset by higher deformation costs. Analyses of ρ(<i>r</i>) showed that stabilization arises from networks of spatially distributed weak interactions rather than from strong directional intermolecular hydrogen bonds. These findings offer a detailed view of β-CD host-guest recognition within a carrier context, guiding the design of β-cyclodextrin-based systems to improve the formulation, stability, and therapeutic effectiveness of drugs in type 2 diabetes mellitus.