Aromatic interactions impact ligand binding and function at serotonin 5-HT_2C G protein-coupled receptors: Receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

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-HT_2A receptors, antipsychotic effects are associated with antagonists - in fact, 5-HT_2A agonists can cause hallucinations and 5-HT_2B 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-HT_2C-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-HT_2C receptors.