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

Abstract

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 has not been reported. To predict and validate molecular determinants for 5-HT_2C-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-HT_2C receptors.

Keywords: Aromatic Interactions; F6.51; F6.52; GPCR; Serotonin 5-HT2C; W6.48; docking; drug design; homology modeling; molecular dynamics.