Rational design of k-casein peptides to modulate GSK-3B dynamics for Alzheimer's therapy

Area of Science:

• Biochemistry
• Neuroscience
• Drug Discovery

Background:

• Glycogen synthase kinase 3 beta (GSK-3β) is a critical therapeutic target for Alzheimer's disease (AD) due to its role in tau hyperphosphorylation and synaptic dysfunction.
• Identifying effective inhibitors for GSK-3β is crucial for developing novel AD treatments.

Purpose of the Study:

• To rationally design and computationally evaluate food-derived peptide inhibitors targeting GSK-3β for potential Alzheimer's disease therapy.
• To identify specific peptide modifications that enhance binding affinity and inhibitory potential against GSK-3β.

Main Methods:

• Utilized HADDOCK and molecular dynamics (MD) simulations for peptide-target interaction analysis.
• Employed MM/PBSA and ΔΔG-based substitution to analyze binding affinities and guide peptide library generation.
• Applied toxicity and allergenicity filters to screen potential drug candidates.

Main Results:

• Identified four unfavorable mutation sites in a κ-casein-derived peptide (LALTLPFLGA).
• Generated and screened a peptide library, prioritizing PEP8, PEP36, PEP40, and PEP44.
• PEP8 and PEP44 demonstrated superior binding affinities and interaction networks with GSK-3β, with PEP8 showing 21 contacts and PEP44 showing 19 contacts.
• MD simulations indicated that PEP8 and PEP44 induce conformational changes, potentially hindering substrate binding, and MMPBSA confirmed their strong complex formation.

Conclusions:

• PEP8 and PEP44, derived from κ-casein, are identified as promising inhibitors of GSK-3β.
• The study demonstrates a successful computational pipeline for designing food-derived peptides as potential multifunctional agents for Alzheimer's disease.