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Conformation-activity relationships of cyclic dermorphin analogues
1Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
Biopolymers
|January 1, 1990
Summary
This study analyzed cyclic tetrapeptides related to dermorphin analogues. High mu-receptor affinity in analogues correlated with a specific tilted stacking interaction between aromatic rings in their low-energy conformations.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Pharmacology
Background:
- Cyclic tetrapeptides are structurally diverse and exhibit varied mu-receptor affinities.
- Dermorphin analogues are known for their high mu-receptor selectivity.
Purpose of the Study:
- To perform a theoretical conformational analysis of nine cyclic tetrapeptides.
- To understand the structural basis for mu-receptor affinity and selectivity in these analogues.
Main Methods:
- Molecular mechanics computational study.
- Systematic conformational search and energy minimization.
- Analysis of low-energy conformers and side-chain interactions.
Main Results:
- Constrained 11-13-membered ring structures were identified.
- Limited low-energy conformational families were found for all compounds.
- Five high-affinity analogues showed a tilted stacking interaction between Tyr1 and Phe3 aromatic rings in their lowest energy conformations.
Conclusions:
- A tilted stacking interaction between Tyr1 and Phe3 aromatic rings is crucial for high mu-receptor affinity.
- This specific conformational feature is absent in analogues with poor mu-receptor affinity.