Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors: Receptor homology modeling, 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-HT2C 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-HT2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function, however, ligand interactions with these residues at the 5-HT2C receptor 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-HT2C receptors.