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Structure-property model for membrane partitioning of oligopeptides
L H Alifrangis1, I T Christensen, A Berglund
1Departments of Medicinal Chemistry and Pharmaceutics, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark. lhk@mail.dfh.dk
Journal of Medicinal Chemistry
|January 14, 2000
Summary
This study developed a model predicting how oligopeptides cross membranes. It found that high hydrogen-bonding potential and negative charges hinder partitioning, while hydrophobicity aids it, crucial for oral drug design.
Area of Science:
- Medicinal Chemistry
- Pharmacokinetics
- Computational Chemistry
Background:
- Oligopeptides show promise as peptide-like drugs but often have poor oral bioavailability.
- Understanding membrane partitioning is key to predicting drug absorption and designing effective therapeutics.
Purpose of the Study:
- To develop a predictive structure-property model for oligopeptide membrane partitioning.
- To identify key molecular descriptors influencing peptide membrane permeability.
Main Methods:
- Design of 20 tetrapeptides with N-methylations using D-optimal design.
- Assessment of membrane partitioning via immobilized artificial membrane (IAM) and immobilized liposome chromatography (ILC).
- Analysis of structure-property relationships using partial least-squares projection to latent structures (PLS) with molecular descriptors (surface area, Molsurf, Volsurf).
Main Results:
- Developed statistically robust models for membrane partitioning.
- Identified that high hydrogen-bonding potential and negative charges impede membrane partitioning.
- Determined that hydrophobic parameters enhance membrane partitioning.
Conclusions:
- The developed model accurately predicts oligopeptide membrane partitioning based on molecular descriptors.
- Findings align with known drug absorption principles.
- Implications for designing peptide-like drugs with improved oral bioavailability.