The molecular mechanism behind the stabilization of insulin by choline and geranate (CAGE) ionic liquids – computational insights into oral insulin drug formulation

Abstract

Insulin is a principal hormone that is involved in the regulation of glucose levels in the blood. Oral insulin formulation is a recent development in drug delivery systems. Biocompatible choline-based ionic liquids (ILs) show promising antibacterial activity and are useful for oral and transdermal drug delivery applications. Choline and geranate (CAGE) ILs enhance the stability and oral efficacy of insulin delivery. The molecular mechanism behind insulin formulation in the oral form is at issue. In the present work, the molecular-level understanding of CAGE ILs in insulin is scrutinized by employing atomistic molecular dynamics (MD) simulations. To identify the stability of insulin in an IL medium, we have studied a series of concentration (mole fraction 0.05-1.00) of CAGE ILs with an insulin dimer. It can be well evidenced from the experimental reports that in an aqueous medium, there is a refashioning of CAGE nanostructures at 0.50 mole fraction. It is found from our calculations that the first solvation shell of insulin is readily occupied by choline and geranate ions in the presence of water. Moreover, the geranate ions strongly interacted with the water molecules and thereby, eliminating the intermolecular hydrogen bonding (H-bonding) interactions towards the insulin at 0.30-0.50 mole fraction of CAGE ILs. The most desirable 0.30-0.50 mole fraction of CAGE invigorates water-mediated H-bonding interactions with geranate ions, which also enhances the electrostatic behavior around the vicinity of the insulin dimer. These important findings can help in the development of oral insulin drug delivery and related applications.