Systematic Search for Blood-Brain Barrier Modulating Peptides Based on Exhaustive E-Cadherin Domain-Domain Docking

Area of Science:

• Biochemistry
• Computational Biology
• Pharmacology

Background:

• Intercellular junctions, including those involving E- and VE-cadherins, are vital for biological barriers like the blood-brain barrier (BBB).
• The BBB restricts the passage of therapeutic molecules into the central nervous system.
• Previous studies identified peptides that modulate BBB junctions, improving molecule permeation.

Purpose of the Study:

• To systematically search for novel peptides that disrupt E-cadherin interactions at the BBB.
• To enhance BBB permeability for improved drug delivery to the brain using computational methods.

Main Methods:

• Computational protein-protein docking was used to analyze interactions within the first two extracellular domains (EC12) of human E-cadherin.
• 115 candidate peptides were proposed based on predicted binding interfaces.
• Peptides were redocked, and binding affinities were analyzed using various protein-peptide docking methods.

Main Results:

• Several peptides demonstrated strong binding affinity to E-cadherin EC12.
• One synthesized peptide, WVIPPIS, exhibited a dissociation constant (KD) of 239 nM for the E-cadherin EC1 domain.
• This peptide showed a binding free energy of -9.07 kcal/mol at 25 °C, indicating a domain-swapping interaction.

Conclusions:

• A systematic computational approach was developed for generating peptides that disrupt BBB junctions.
• The identified peptides show high potential for enhancing BBB permeability.
• These findings support the development of novel strategies for brain drug delivery.