title: Insights into the structure and pharmacology of the human trace amine-associated receptor 1 (hTAAR1): homology modelling and docking studies.
abstract: Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that belongs to the family of TAAR receptors and responds to a class of compounds called trace amines, such as β-phenylethylamine (β-PEA) and 3-iodothyronamine (T(1)AM). The receptor is known to have a very rich pharmacology and could be also activated by other classes of compounds, including adrenergic and serotonergic ligands. It is expected that targeting TAAR1 could provide a novel pharmacological approach to correct monoaminergic dysfunctions found in several brain disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder and Parkinson's disease. Only recently, the first selective TAAR1 agonist RO5166017 has been identified. To explore the molecular mechanisms of protein-agonist interaction and speed up the identification of new chemical entities acting on this biomolecular target, we derived a homology model for the hTAAR1. The putative protein-binding site has been explored by comparing the hTAAR1 model with the β(2)-adrenoreceptor binding site, available by X-ray crystallization studies, and with the homology modelled 5HT(1A) receptor. The obtained results, in tandem with docking studies performed with RO5166017, β-PEA and T(1)AM, provided an opportunity to reasonably identify the hTAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV n. 3, 16132, Genova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.forename: Stefano
authors.initials: S
authors.lastname: Espinoza
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.forename: Livio
authors.initials: L
authors.lastname: Brasili
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010080:Oxazoles / Q000737:chemistry* / Q000378:metabolism; D010627:Phenethylamines / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D016415:Sequence Alignment; D013970:Thyronines / Q000737:chemistry* / Q000378:metabolism; D000095383:Trace Amine-Associated Receptors
chemical_list: D010080:Oxazoles; D010627:Phenethylamines; D044282:Receptor, Serotonin, 5-HT1A; D043562:Receptors, G-Protein-Coupled; D013970:Thyronines; D000095383:Trace Amine-Associated Receptors; C487948:3-iodothyronamine; C583451:RO5166017; C029261:phenethylamine