Insulin Complexation with Cyclodextrins-A Molecular Modeling Approach.

Area of Science:

• Pharmaceutical Science
• Biochemistry
• Computational Chemistry

Background:

• Diabetes mellitus affects approximately 5% of the global population worldwide.
• Insulin monomer, the active form of insulin medication, is unstable and prone to misfolding into inactive β-sheet rich structures under stress (e.g., high temperature, prolonged storage).
• This misfolding can lead to pharmaceutical inactivity and potentially amyloid fibrillation, compromising diabetes treatment.

Purpose of the Study:

• To investigate the complexation of insulin monomers with various pharmaceutical cyclodextrins (native, methyl-, hydroxyethyl-, hydroxypropyl-, and sulfobutylether-β-cyclodextrin).
• To determine the optimal cyclodextrin type and molar ratio for forming stable insulin complexes using in silico methods.
• To predict the complex conformation and identify intermolecular hydrogen bonds crucial for stabilization.

Main Methods:

• Utilized AutoDock molecular modeling software for in silico simulations.
• Assessed the binding affinity and interaction patterns between insulin monomers and different β-cyclodextrin derivatives.
• Analyzed predicted complex conformations and hydrogen bond formation.

Main Results:

• Insulin monomers can form stable complexes with hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin.
• Optimal complexation involves 5-7 molecules of these specific cyclodextrin derivatives per insulin monomer.
• The formation of these complexes shows potential to inhibit or delay insulin amyloid fibrillation.

Conclusions:

• Hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin are promising excipients for stabilizing insulin monomers.
• Complexation with these cyclodextrins can enhance insulin stability and prevent pharmaceutically inactive conformations.
• This approach offers a potential strategy to improve the shelf-life and efficacy of insulin-based diabetes medications.