Conformational analysis and automated receptor docking of selective arylacetamide-based κ-opioid agonists

Govindan Subramanian, M. Germana Paterlini, Dennis L. Larson, Philip S. Portoghese, David M. Ferguson

Research output: Contribution to journalArticle

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Abstract

The three-dimensional structure, dynamics, and binding modes of representative κ-opioid agonists of the arylacetamide class (U50,488; U69,593; U62,066; CI-977; ICI199,441; ICI197,067; BRL52,537; and BRL52,656) have been investigated using molecular modeling techniques. Systematic exploration of the conformational space of the ligand combined with molecular dynamics (MD) simulations in water revealed consistent conformational preferences for all the κ-agonists in this series. The results were further compared with available X-ray and 1D-and 2D-NMR data to identify potential 'lead' conformers for molecular docking. Ligand binding modes were initially determined using automated docking of two of the ligands (U50,488 and BRL52,537) to the κ-opioid receptor. Extrapolation of the predicted binding mode to other members in this ligand series revealed similar docking preferences, with each ligand docked along the receptor helical axis. The binding modes were further refined using MD simulations of the receptor- ligand complexes. The results show a that salt bridge is formed between the amino proton of the ligands and the carboxylate group of Asp138 in TM3. This interaction most likely serves as a key anchoring point for the agonist association. Additional ligand contacts were noted with κ-specific residues Ile294, Leu295, and Ala298, which may, in part, explain the κ-selectivity in this series. In comparing the arylacetamides with opiate-based ligands, no evidence was found to link these classes through a common binding motif (except for the ion pair). The binding site model was also applied to explain the enantiomeric preference of U50,488 and to provide insight to the μ/κ- selectivity of representative ligands in this series. Overall, the results provide a structure-based rationale for ligand recognition that is consistent both with site-directed mutagenesis experiments and structure-function relationship data.

Original languageEnglish (US)
Pages (from-to)4777-4789
Number of pages13
JournalJournal of Medicinal Chemistry
Volume41
Issue number24
DOIs
StatePublished - Nov 19 1998

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Opioid Analgesics
Ligands
Molecular Dynamics Simulation
Opiate Alkaloids
Space Flight
Opioid Receptors
Site-Directed Mutagenesis
Protons
Salts
Binding Sites
X-Rays
Ions
Water

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Conformational analysis and automated receptor docking of selective arylacetamide-based κ-opioid agonists. / Subramanian, Govindan; Germana Paterlini, M.; Larson, Dennis L.; Portoghese, Philip S.; Ferguson, David M.

In: Journal of Medicinal Chemistry, Vol. 41, No. 24, 19.11.1998, p. 4777-4789.

Research output: Contribution to journalArticle

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abstract = "The three-dimensional structure, dynamics, and binding modes of representative κ-opioid agonists of the arylacetamide class (U50,488; U69,593; U62,066; CI-977; ICI199,441; ICI197,067; BRL52,537; and BRL52,656) have been investigated using molecular modeling techniques. Systematic exploration of the conformational space of the ligand combined with molecular dynamics (MD) simulations in water revealed consistent conformational preferences for all the κ-agonists in this series. The results were further compared with available X-ray and 1D-and 2D-NMR data to identify potential 'lead' conformers for molecular docking. Ligand binding modes were initially determined using automated docking of two of the ligands (U50,488 and BRL52,537) to the κ-opioid receptor. Extrapolation of the predicted binding mode to other members in this ligand series revealed similar docking preferences, with each ligand docked along the receptor helical axis. The binding modes were further refined using MD simulations of the receptor- ligand complexes. The results show a that salt bridge is formed between the amino proton of the ligands and the carboxylate group of Asp138 in TM3. This interaction most likely serves as a key anchoring point for the agonist association. Additional ligand contacts were noted with κ-specific residues Ile294, Leu295, and Ala298, which may, in part, explain the κ-selectivity in this series. In comparing the arylacetamides with opiate-based ligands, no evidence was found to link these classes through a common binding motif (except for the ion pair). The binding site model was also applied to explain the enantiomeric preference of U50,488 and to provide insight to the μ/κ- selectivity of representative ligands in this series. Overall, the results provide a structure-based rationale for ligand recognition that is consistent both with site-directed mutagenesis experiments and structure-function relationship data.",
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