Human serotonin 5-HT2C G protein-coupled receptor homology model from the β2 adrenoceptor structure: Ligand docking and mutagenesis studies

Tania Córdova-Sintjago, Nancy Villa, Clinton Canal, Raymond Booth

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Activation of the serotonin (5-hydroxytryptamine, 5-HT) 5HT2C G protein-coupled receptor (GPCR) is proposed as novel pharmacotherapy for obesity and neuropsychiatric disorders. In contrast, activation of the 5-HT 2A and 5-HT2B GPCRs is associated with untoward hallucinogenic and cardiopulmonary effects, respectively. There is no crystal structure available to guide design of 5-HT2C receptor-specific ligands. For this reason, a homology model of the 5-HT2C receptor was built based on the crystal structure of the human β2 adrenoceptor GPCR to delineate molecular determinants of ligand-receptor interactions for drug design purposes. Computational and experimental studies were carried out to validate the model. Binding of N(CH3) 2-PAT [(1R, 3S)-(-)-trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4- tetrahydronaphthalene], a novel 5-HT2C agonist/5-HT2A/2B inverse agonist, and its secondary [NH(CH3)-PAT] and primary (NH 2-PAT) amine analogs were studied at the 5-HT2C wild type (WT) and D3.32A, S3.36A, and Y7.43A 5-HT2C point-mutated receptors. Reference ligands included the tertiary amines lisuride and mesulergine and the primary amine 5-HT. Modeling results indicated that 5-HT2C residues D3.32, S3.36, and Y7.43 play a role in ligand binding. Experimental ligand binding results with WT and point-mutated receptors confirmed the impact of D3.32, S3.36, and Y7.43 on ligand affinity.

Original languageEnglish (US)
Pages (from-to)140-149
Number of pages10
JournalInternational Journal of Quantum Chemistry
Volume112
Issue number1
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

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Keywords

  • GPCR homology modeling
  • drug design
  • serotonin 5-HT receptor

ASJC Scopus subject areas

  • Atomic and Molecular Physics, and Optics
  • Condensed Matter Physics
  • Physical and Theoretical Chemistry

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