title: Insights into binding modes of 5-HT2c receptor antagonists with ligand-based and receptor-based methods.
abstract: 5-hydroxytryptamine-2c (5-HT2c) receptor antagonists have clinical utility in the management of nervous system. In this work, ligand-based and receptor-based methods were used to investigate the binding mode of h5-HT2c receptor antagonists. First, the pharmacophore modeling of the h5-HT2c receptor antagonists was carried out by CATALYST. Then, the h5-HT2c antagonists were docked to the h5-HT2c receptor model. Subsequently, the comprehensive analysis of the pharmacophore and docking results revealed the structure-activity relationship of 5-HT2c receptor antagonists and the key residues involved in the interactions. For example, three hydrophobic points in the ligands corresponded to the region surrounded by Val135, Val208, Phe214, Ala222, Phe327, Phe328 and Val354 of the h5-HT2c receptor. The carbonyl group of compound 1 formed a hydrogen bond with Asn331. The nitrogen atom in the piperidine of compound 1 corresponding to the positive ionizable position of the best pharmacophore formed the electrostatic interactions with the carbonyl of Asp134, Asn331 and Val354, and with the hydroxyl group of Ser334. In addition, a predictive CoMFA model was developed based on the 24 compounds that were used as the training set in the pharmacophore modeling. Our results were not only useful to explore the detailed mechanism of the interactions between the h5-HT2c receptor and antagonists, but also provided suggestions in the discovery of novel 5-HT2c receptor antagonists.
authors.affiliation: School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Fangfang
authors.initials: F
authors.lastname: Jin
authors.forename: Cui
authors.initials: C
authors.lastname: Li
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Guixia
authors.initials: G
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry* / Q000378:metabolism; D015203:Reproducibility of Results; D016415:Sequence Alignment; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists