title: Identification of structural determinants of ligand selectivity in 5-HT₂ receptor subtypes on the basis of protein-ligand interactions.
abstract: Drug selectivity is one of the most critical improvement steps in drug development. The 5-hydroxytryptamine 2 (5-HT₂) receptor has 3 subtypes that exhibit different pharmacological functions. Because of their high amino acid sequence similarity, designing small molecules that selectively activate only 1 receptor among the 3 subtypes is difficult. We performed homology modeling of the 5-HT₂ receptor subtypes using the β₂-adrenergic receptor as a template to identify differences in active sites that may influence 5-HT₂ receptor agonist selectivity. A subset of selective 5-HT₂ agonists was docked into the modeled protein structures to investigate their interactions with each receptor. Subtype-specific active site residues at positions xl2.54, 5.39, and 5.46 interacted differently with each ligand. Molecular dynamics simulations revealed that position 5.46 of the 5-HT(2A) receptor interacted more favorably with selective 5-HT(2A) agonists than with selective 5-HT(2B) agonists. These computationally obtained insights provided clues to improving agonist selectivity for specific pharmacological action at 5-HT₂ receptors.
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
authors.forename: Jae Wan
authors.initials: JW
authors.lastname: Jang
authors.forename: Min Sup
authors.initials: MS
authors.lastname: Kim
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Art E
authors.initials: AE
authors.lastname: Cho
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry*; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry*; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D012243:Rhodopsin / Q000737:chemistry; D016415:Sequence Alignment; D058826:Serotonin 5-HT2 Receptor Agonists / Q000737:chemistry*; D040681:Structural Homology, Protein
chemical_list: D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D018343:Receptors, Adrenergic, beta-2; D058826:Serotonin 5-HT2 Receptor Agonists; D012243:Rhodopsin