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Insights into the Structure and Pharmacology of the Human Trace Amine‐Associated Receptor 1 ( h TAAR1): Homology Modelling and Docking Studies
Author(s) -
Cichero Elena,
Espinoza Stefano,
Gainetdinov Raul R.,
Brasili Livio,
Fossa Paola
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12018
Subject(s) - docking (animal) , homology modeling , receptor , computational biology , monoaminergic , pharmacophore , g protein coupled receptor , agonist , pharmacology , chemistry , biology , biochemistry , serotonin , medicine , enzyme , nursing
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 h TAAR1. The putative protein‐binding site has been explored by comparing the h TAAR1 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 h TAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists.