A three-dimensional model of the δ-opioid pharmacophore: Comparative molecular modeling of peptide and nonpeptide ligands

Mark D. Shenderovich, Subo Liao, Xinhua Qian, Victor J Hruby

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

A comparative molecular modeling study of δ-opioid ligands was performed under the assumption that potent peptide and nonpeptide agonists may have common three-dimensional (3D) arrangement of pharmacophore groups upon binding to the δ-receptor. Low-energy conformations of the agonists 7- spiroindanyloxymorphone (SlOM) and 2-methyl-4a-α-(3-hydroxyphenyl)- 1,2,3,4,4a, 5,12,12a-α-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67), and a partial agonist oxomorphindole (OMI) were determined by high- temperature molecular dynamics (MD). A good spatial overlap was found for the pharmacophore groups of SlOM, TAN-67, and OMI, including the basic nitrogen, phenol hydroxyl, and two aromatic ring. Based on this overlap we proposed a 3D pharmacophore model for nonpeptide δ-opioid agonists with a distance of 7.0 ± 1.3 Å between the two aromatic rings and of 8.2 ± 1.0 Å between the nitrogen and phenyl ring. The potent and highly δ-opioid receptor selective agonist [(2S, 3R)-TMT1]DPDPE, which shares global backbone constraints of the 14-membered disulfide cycle and a strong preference for the trans rotamer of the TMT-1 side chain, was chosen as a peptide template of the δ-opioid pharmacophore. Extensive MD simulations at 300 K with the AMBER force field were performed for [(2S, 3R)-TMT1]DPDPE and the less potent [(2S,3S)- TMT1]DPDPE analogue. Multiple MD trajectories were collected for each peptide starting from the x-ray structures of DPDPE and [L-Ala3]DPDPE and from models proposed in the literature. Low-energy MD conformations were filtered by the nonpeptide pharmacophore query and then directly superimposed with SIOM, OMI, and TAN-67. Two conformers of [(2S,3R)-TMT1]DPDPE that showed the best overlap with the nonpeptide pharmacophore (rms deviation ≤ 1.0 Å for N,O atoms and centroids of two aromatic rings) were selected as possible δ-receptor binding conformations. These conformations have similar backbone structures, and trans rotamers of the TMT1 side-chain group. They are reasonably close to the crystal structure of [L-Ala3]DPDPE, and differ significantly from the crystal structure of DPDPE. The conformer with a gauche(-) rotamer of Phe4 is most consistent with structure-activity relationships of δ-opioid peptides. The proposed 3D models were used for rational design of new nonpeptide δ-receptor ligands. (C) 2000 John Wiley and Sons, Inc.

Original languageEnglish (US)
Pages (from-to)565-580
Number of pages16
JournalBiopolymers - Peptide Science Section
Volume53
Issue number7
DOIs
StatePublished - 2000

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D-Penicillamine (2,5)-Enkephalin
Molecular modeling
Opioid Analgesics
Peptides
Conformations
Molecular dynamics
Ligands
Molecular Dynamics Simulation
Crystal structure
Nitrogen
Opioid Peptides
Phenols
Trajectories
Molecular Conformation
X rays
Atoms
Computer simulation
Opioid Receptors
Structure-Activity Relationship
Phenol

Keywords

  • δ-opioid pharmacophore
  • Agonist
  • Ligand
  • Molecular modeling
  • Nonpeptide
  • Peptide

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics

Cite this

A three-dimensional model of the δ-opioid pharmacophore : Comparative molecular modeling of peptide and nonpeptide ligands. / Shenderovich, Mark D.; Liao, Subo; Qian, Xinhua; Hruby, Victor J.

In: Biopolymers - Peptide Science Section, Vol. 53, No. 7, 2000, p. 565-580.

Research output: Contribution to journalArticle

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AU - Hruby, Victor J

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N2 - A comparative molecular modeling study of δ-opioid ligands was performed under the assumption that potent peptide and nonpeptide agonists may have common three-dimensional (3D) arrangement of pharmacophore groups upon binding to the δ-receptor. Low-energy conformations of the agonists 7- spiroindanyloxymorphone (SlOM) and 2-methyl-4a-α-(3-hydroxyphenyl)- 1,2,3,4,4a, 5,12,12a-α-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67), and a partial agonist oxomorphindole (OMI) were determined by high- temperature molecular dynamics (MD). A good spatial overlap was found for the pharmacophore groups of SlOM, TAN-67, and OMI, including the basic nitrogen, phenol hydroxyl, and two aromatic ring. Based on this overlap we proposed a 3D pharmacophore model for nonpeptide δ-opioid agonists with a distance of 7.0 ± 1.3 Å between the two aromatic rings and of 8.2 ± 1.0 Å between the nitrogen and phenyl ring. The potent and highly δ-opioid receptor selective agonist [(2S, 3R)-TMT1]DPDPE, which shares global backbone constraints of the 14-membered disulfide cycle and a strong preference for the trans rotamer of the TMT-1 side chain, was chosen as a peptide template of the δ-opioid pharmacophore. Extensive MD simulations at 300 K with the AMBER force field were performed for [(2S, 3R)-TMT1]DPDPE and the less potent [(2S,3S)- TMT1]DPDPE analogue. Multiple MD trajectories were collected for each peptide starting from the x-ray structures of DPDPE and [L-Ala3]DPDPE and from models proposed in the literature. Low-energy MD conformations were filtered by the nonpeptide pharmacophore query and then directly superimposed with SIOM, OMI, and TAN-67. Two conformers of [(2S,3R)-TMT1]DPDPE that showed the best overlap with the nonpeptide pharmacophore (rms deviation ≤ 1.0 Å for N,O atoms and centroids of two aromatic rings) were selected as possible δ-receptor binding conformations. These conformations have similar backbone structures, and trans rotamers of the TMT1 side-chain group. They are reasonably close to the crystal structure of [L-Ala3]DPDPE, and differ significantly from the crystal structure of DPDPE. The conformer with a gauche(-) rotamer of Phe4 is most consistent with structure-activity relationships of δ-opioid peptides. The proposed 3D models were used for rational design of new nonpeptide δ-receptor ligands. (C) 2000 John Wiley and Sons, Inc.

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KW - δ-opioid pharmacophore

KW - Agonist

KW - Ligand

KW - Molecular modeling

KW - Nonpeptide

KW - Peptide

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