| Abstract [eng] |
Glibenclamide also known as gliburide is a sulphonylurea drug used to treat type 2 diabetes. Glibenclamide's mechanism of action is based on inhibiting membrane adenosine triphosphate (ATP) sensitive potassium ion channels (K_ATP) in liver cells, thus controling insulin secretion and glucose levels in blood. New ways to use this compound for inhibiting headaches or various inflamations are also being found. Unfortunately, glibenclamide is poorly soluble in water (15-24 ug/mL) which makes it harder to find new pharmaceutical applications. To improve glibenclamide's solubility, a biological choline-tryptophanate ionic liquid was added to water, increasing glibenclamide's solubility to 27 mg/mL -- by 130-600 times compared to the solubility in pure water. Discovering what intermolecular interactions result in such increase of solubility would help us understand what ionic liquid properties are responsible for this and how can we adapt more biological ionic liquids to biological systems. One of the main tools for studying intermolecular interactions is nuclear magnetic resonance (NMR) spectroscopy as 1H NMR chemical shifts depend on the surroundings of the molecule. The NMR parameters of two systems: glibenclamide in aqueous solution (Glb_aq) and in ionic liquid mixture with water (Glb_IL/aq) were investigated. The main goal of this study was to find out what intermolecular interactions result in the increase of glibenclamide’s solubility in aqueous mixtures with ionic liquid by using molecular dynamics (MD) simulations and quantum mechanics / molecular mechanics (QM/MM) methods. Constants of tautomeric equilibrium pK_T were calculated for glibenclamide tautomers in aqueous environment and the most stable one of them was found. By analysing the dihedral angles between glibenclamide atoms, it was found that there are no significant changes between the conformations of glibenclamide in Glb_aq and Glb_IL/aq systems, the conformation of the molecule is such which minimises the water accessible surface. The calculated coordination numbers between the glibenclamide and solvent atoms and glibenclamide's magnetic shielding constants let us conclude that the increase of solubility of glibenclamide in ionic liquid mixtures with water is impacted by intermolecular interactions between choline and tryptophanate ions and the amide groups, aromatic rings and cyclohexane cycle of glibenclamide. |
