Structure-activity relationships of endomorphin-1, endomorphin-2 and morphiceptin by molecular dynamics methods

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Abstract

A conformational analysis of endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2, EM1), endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM2) and morphiceptin (Tyr-Pro-Phe-Pro-NH2, MC), as μ-opioid receptor ligands was performed by the simulated annealing (SA) method and solvated molecular dynamics (MD) calculations. In SA experiments, 1000 conformers were generated for each peptide with both cis and trans Tyr-Pro peptide bond isomers. The populations of the conformers in the different regions of the Ramachandran plots and the numbers of the various types of turns and the distribution of distances of the main pharmacophore elements (i.e. phenolic OH of Tyr 1, tyramine N and the aromatic side-chain of Phe3) for the three peptides were compared. EM1 and EM2 seemed to be almost identical in their conformational features, ca. 30% of their conformers possessed turns with a significant ratio of β-turn type III, while in MC a drastic decrease in the number of turns and an increase of the number of extended structures were observed. According to the differences in the Φ33 Ramachandran plots, the Phe3 pharmacophore was affected in MC. Also, a pairwise comparison of the interaction energies between all fragments of the peptides (i.e. between backbone and side-chain fragments of each amino acid residue) showed that the presence of Pro4 in MC initiated increased repulsive interactions toward the Pro2-Phe 3 fragment relative to Phe4 toward the Pro 2-Phe3 and Pro2-Trp3 fragments in EM2 and EM1, respectively, accounting for its decreased opioid activity. The conformational analysis was repeated by isotherm molecular dynamics calculations in a periodic box with a modified GROMOS96 force field. The results support our previous experience.

Original languageEnglish
Pages (from-to)345-353
Number of pages9
JournalJournal of Molecular Structure: THEOCHEM
Volume666-667
DOIs
Publication statusPublished - Dec 29 2003

Keywords

  • Conformational analysis
  • Endomorphin-1
  • Endomorphin-2
  • Intramolecular H-bonds
  • Intramolecular interaction energy
  • Molecular dynamics
  • Morphiceptin
  • Regular and inverse γ-turns
  • Simulated annealing
  • β-turns

ASJC Scopus subject areas

  • Biochemistry
  • Condensed Matter Physics
  • Physical and Theoretical Chemistry

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