Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors

Receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

Tania Córdova-Sintjago, Nancy Villa, Lijuan Fang, Raymond G. Booth

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ∼75% transmembrane (TM) sequence identity. Agonists for 5-HT 2C receptors are under development for psychoses; whereas, at 5-HT2A receptors, antipsychotic effects are associated with antagonists - in fact, 5-HT2A agonists can cause hallucinations and 5-HT2B agonists cause cardiotoxicity. It is known that 5-HT 2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function; however, ligand interactions with these residues at the 5-HT 2C receptor have not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modelling, ligand docking, and molecular dynamics simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT2C receptors.

Original languageEnglish (US)
Pages (from-to)398-407
Number of pages10
JournalMolecular Physics
Volume112
Issue number3-4
DOIs
StatePublished - Feb 16 2014
Externally publishedYes

Fingerprint

serotonin
homology
Molecular Dynamics Simulation
G-Protein-Coupled Receptors
Molecular dynamics
Serotonin
Serotonin 5-HT2 Receptor Agonists
molecular dynamics
Ligands
proteins
ligands
Serotonin Receptors
interactions
Receptor, Serotonin, 5-HT2C
Receptor, Serotonin, 5-HT2A
Serotonin Receptor Agonists
hallucinations
Hallucinations
psychoses
Psychotic Disorders

Keywords

  • Aromatic interactions
  • Docking
  • Drug design
  • F6.51
  • F6.52
  • GPCR
  • Homology modelling
  • Molecular dynamics
  • Serotonin 5-HT
  • W6.48

ASJC Scopus subject areas

  • Biophysics
  • Molecular Biology
  • Condensed Matter Physics
  • Physical and Theoretical Chemistry

Cite this

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title = "Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors: Receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies",
abstract = "The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ∼75{\%} transmembrane (TM) sequence identity. Agonists for 5-HT 2C receptors are under development for psychoses; whereas, at 5-HT2A receptors, antipsychotic effects are associated with antagonists - in fact, 5-HT2A agonists can cause hallucinations and 5-HT2B agonists cause cardiotoxicity. It is known that 5-HT 2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function; however, ligand interactions with these residues at the 5-HT 2C receptor have not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modelling, ligand docking, and molecular dynamics simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT2C receptors.",
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