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 p-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 p-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 p-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(r) 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.