Molecular determinants for ligand binding at serotonin 5-HT2A and 5-HT2C GPCRs: Experimental affinity results analyzed by molecular modeling and ligand docking studies

• Published in: International journal of quantum chemistry 2012-12, Vol.112 (24), p.3807-3814
• Main Authors: Córdova-Sintjago, Tania, Sakhuja, Rajeev, Kondabolu, Krishnakanth, Canal, Clinton E., Booth, Raymond G.
• Format: Article
• Language: English
• Subjects: 5-HT2C; Chemistry; docking; drug design; GPCR; homology modelling; ligand-receptor interactions; molecular dynamics; phosphatidyl choline bilayer; Physical chemistry; Quantum physics; serotonin 5-HT2A
• ISSN: 0020-7608; 1097-461X
• DOI: 10.1002/qua.24237

Ligands that activate the serotonin 5‐HT2C G protein‐coupled receptor (GPCR) may be therapeutic for psychoses, addiction, and other neuropsychiatric disorders. Ligands that are antagonists at the closely related 5‐HT2A GPCR also may treat neuropsychiatric disorders; in contrast, 5‐HT2A activation may cause hallucinations. 5‐HT2C‐specific agonist drug design is challenging because 5‐HT2 GPCRs 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‐HT2 GPCRs, 5‐HT2A, and 5‐HT2C homology models were built from the β2‐adrenergic GPCR crystal structure and equilibrated in a lipid phosphatidyl choline bilayer performing molecular dynamics simulations. Ligand docking studies at the 5‐HT2 receptor models were conducted with the (2R, 4S)‐ and (2S, 4R)‐enantiomers of the novel 5‐HT2C agonist/5‐HT2A/2B antagonist trans‐4‐phenyl‐N,N‐dimethyl‐2‐aminotetralin (PAT) and its 4′‐chlorophenyl congners. Results indicate PAT–5‐HT2 molecular 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. © 2012 Wiley Periodicals, Inc. The neurotransmitter serotonin mediates some of its psychological effects by activation of the 5‐HT2 family of G protein coupled receptors (GPCRs). In this work, the overall receptor structures and ligand binding sites of several 5‐HT2 GPCRs for drug are compared via homology modeling, molecular dynamics, and docking studies. This approach produces reliably predictable homology models, useful for the study of drug–receptor interaction for drug design purposes.