title: Molecular Determinants for Ligand Binding at Serotonin 5-HT2Aand 5-HT2CGPCRs: Experimental Affinity Results Analyzed by Molecular Modeling and Ligand Docking Studies.
abstract: Ligands that activate the serotonin 5-HT2CG protein-coupled receptor (GPCR) may be therapeutic for psychoses, addiction, and other neuropsychiatric disorders. Ligands that are antagonists at the closely related 5-HT2AGPCR also may treat neuropsychiatric disorders; in contrast, 5-HT2Aactivation may cause hallucinations. 5-HT2C-specific agonist drug design is challenging because 5-HT2GPCRs share 80% transmembrane (TM) homology, same second messenger signaling, and no crystal structures are reported. To help delineate molecular determinants underlying differential binding and activation of 5-HT2GPCRs, 5-HT2A, and 5-HT2Chomology models were built from theβ2-adrenergic GPCR crystal structure and equilibrated in a lipid phosphatidyl choline bilayer performing molecular dynamics simulations. Ligand docking studies at the 5-HT2receptor models were conducted with the (2R, 4S)- and (2S, 4R)-enantiomers of the novel 5-HT2Cagonist/5-HT2A/2Bantagonisttrans-4-phenyl-N,N-dimethyl-2-aminotetralin (PAT) and its 4'-chlorophenyl congners. Results indicate PAT-5-HT2molecular interactions especially in TM domain V are important for the (2R, 4S) enantiomer, whereas, TM domain VI and VII interactions are more important for the (2S, 4R) enantiomer.
authors.affiliation: Department of Medicinal Chemistry. College of Pharmacy, University of Florida, Gainesville, Florida 32610.
authors.forename: Tania
authors.initials: T
authors.lastname: Córdova-Sintjago
authors.forename: Rajeev
authors.initials: R
authors.lastname: Sakhuja
authors.forename: Krishnakanth
authors.initials: K
authors.lastname: Kondabolu
authors.forename: Clinton E
authors.initials: CE
authors.lastname: Canal
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Booth
keywords: 5-HT2C; GPCR; docking; drug design; homology modelling; ligand–receptor interactions; molecular dynamics; phosphatidyl choline bilayer; serotonin 5-HT2A
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