Characterization of Peptide-Preservative Interaction by AlphaFold, Molecular Dynamics Simulation, and NMR...

Area of Science:

• Pharmaceutical Sciences
• Computational Chemistry
• Biophysics

Background:

• Novel antiobesity medications are crucial for treating metabolic disorders like type 2 diabetes.
• Multiple-dose formulations with preservatives enhance medication accessibility and affordability.
• Peptide-preservative interactions can compromise drug stability and efficacy.

Purpose of the Study:

• To introduce a computational framework for investigating peptide-preservative interactions.
• To elucidate the impact of preservatives (benzyl alcohol and phenol) on incretin peptide stability.
• To provide insights for developing stable multiple-dose peptide formulations.

Main Methods:

• Molecular Dynamics (MD) simulations to model peptide-preservative interactions.
• Nuclear Magnetic Resonance (NMR) data integration to validate simulation findings.
• Analysis of interaction frequencies and structural perturbations.

Main Results:

• Phenol showed significantly higher interaction frequency with the peptide than benzyl alcohol.
• Phenol disrupted stabilizing hydrogen bonds and increased hydrophobic surface exposure, risking peptide stability.
• Specific residues (Asp15, Ile17, Leu26, Ile27) showed higher contact with phenol, correlating with stability differences.

Conclusions:

• The computational framework effectively predicts peptide stability in preserved formulations.
• Phenol presents a greater stability risk to therapeutic peptides compared to benzyl alcohol.
• This approach aids in designing robust, stable multiple-dose peptide drug products.