title: Aromatic interactions impact ligand binding and function at serotonin 5-HT2CG protein-coupled receptors: Receptor homology modeling, ligand docking, and molecular dynamics results validated by experimental studies.
abstract: The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ~75% transmembrane (TM) sequence identity. Agonists for 5-HT2Creceptors are under development for psychoses, whereas, at 5-HT2Areceptors, antipsychotic effects are associated with antagonists-in fact, 5-HT2Aagonists can cause hallucinations and 5-HT2Bagonists cause cardiotoxicity. It is known that 5-HT2ATM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function, however, ligand interactions with these residues at the 5-HT2Creceptor has not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modeling, ligand docking, and molecular dynamics (MD) 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-HT2Creceptors.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610 USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Córdova-Sintjago
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610 USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Villa
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610 USA.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610 USA ; Center for Drug Discovery, Departments of Pharmaceutical Sciences, and, Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115 USA.
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Booth
keywords: Aromatic Interactions; F6.51; F6.52; GPCR; Serotonin 5-HT2C; W6.48; docking; drug design; homology modeling; molecular dynamics
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