Structure-activity relationships of Leu-enkephalin analog with (4-carboxamido)phenylalanine substituted for tyrosine

A molecular dynamics study

Yun-Che Wang, Yng Ching Wu, Che Chia Yeh, Chi-Chuan Hwang

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Motivated by recent experimental work on Leu-Enkephalin modification with (4-Carboxamido)phenylalanine (Cpa), we perform MD simulations to study the structure-activity relationships of the [Cpa1, Leu 5]-enkephalin (Cpa-LE) for better understandings of the binding affinity in δ-selective opioid ligands. Recently, Tyr1 substituted into Cpa1 form was experimentally found to be the first example of an amino acid that acts as a surrogate for Tyr1 in opioid peptide ligands, which challenges a long-standing belief that a phenolic residue is required for high affinity binding. Our simulations show the Cpa-LE structure in aqueous solution revealed that the occurrence of single-bend packed state can be stabilized by an intramolecular hydrogen bond from Leu 5-NH to Gly2-CO (5→2). In addition, an intramolecular sidechain to backbone hydrogen bond, i.e., hydrogen bond binding between the sidechain carbonyl CO group of the Cpa residue and backbone amide NH group of the Phe residue was examined. Furthermore, the hydration effects of carboxamido group (CONH2) for Cpa residue and 5→2 hydrogen bond were calculated via the solute-solvent radial distribution functions g α-β (r), providing direct evidence of strong hydrogen bond interactions. Our simulation results further reveal the χ1 rotamers of the Cpa1 and Phe4 that show preferences for trans and gauche (-), respectively. Finally, we elucidate the probability distributions of two aromatic rings among the Cpa-LE, Leu-enkephalin, and 8 pharmacophore model. The results show that modified the Tyr1 to Cpa1 can lead to increase the potency and selectivity for δ-opioid receptor (DOR), consistent with experimental findings.

Original languageEnglish
Pages (from-to)231-239
Number of pages9
JournalBiopolymers
Volume86
Issue number3
DOIs
Publication statusPublished - 2007 Jun 15

Fingerprint

Leucine Enkephalin
Molecular Dynamics Simulation
Structure-Activity Relationship
Tyrosine
Molecular dynamics
Hydrogen
Hydrogen bonds
Carbon Monoxide
Ligands
Opioid Peptides
Opioid Receptors
Amides
Hydration
Probability distributions
Opioid Analgesics
Distribution functions
Amino acids
(4-carboxamido)phenylalanine
Amino Acids

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Biomaterials
  • Organic Chemistry

Cite this

@article{30f27256709a459ebf72f83e686e2b83,
title = "Structure-activity relationships of Leu-enkephalin analog with (4-carboxamido)phenylalanine substituted for tyrosine: A molecular dynamics study",
abstract = "Motivated by recent experimental work on Leu-Enkephalin modification with (4-Carboxamido)phenylalanine (Cpa), we perform MD simulations to study the structure-activity relationships of the [Cpa1, Leu 5]-enkephalin (Cpa-LE) for better understandings of the binding affinity in δ-selective opioid ligands. Recently, Tyr1 substituted into Cpa1 form was experimentally found to be the first example of an amino acid that acts as a surrogate for Tyr1 in opioid peptide ligands, which challenges a long-standing belief that a phenolic residue is required for high affinity binding. Our simulations show the Cpa-LE structure in aqueous solution revealed that the occurrence of single-bend packed state can be stabilized by an intramolecular hydrogen bond from Leu 5-NH to Gly2-CO (5→2). In addition, an intramolecular sidechain to backbone hydrogen bond, i.e., hydrogen bond binding between the sidechain carbonyl CO group of the Cpa residue and backbone amide NH group of the Phe residue was examined. Furthermore, the hydration effects of carboxamido group (CONH2) for Cpa residue and 5→2 hydrogen bond were calculated via the solute-solvent radial distribution functions g α-β (r), providing direct evidence of strong hydrogen bond interactions. Our simulation results further reveal the χ1 rotamers of the Cpa1 and Phe4 that show preferences for trans and gauche (-), respectively. Finally, we elucidate the probability distributions of two aromatic rings among the Cpa-LE, Leu-enkephalin, and 8 pharmacophore model. The results show that modified the Tyr1 to Cpa1 can lead to increase the potency and selectivity for δ-opioid receptor (DOR), consistent with experimental findings.",
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Structure-activity relationships of Leu-enkephalin analog with (4-carboxamido)phenylalanine substituted for tyrosine : A molecular dynamics study. / Wang, Yun-Che; Wu, Yng Ching; Yeh, Che Chia; Hwang, Chi-Chuan.

In: Biopolymers, Vol. 86, No. 3, 15.06.2007, p. 231-239.

Research output: Contribution to journalArticle

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