TY - JOUR

T1 - Insights into the Structure and Pharmacology of the Human Trace Amine-Associated Receptor 1 (hTAAR1)

T2 - Homology Modelling and Docking Studies

AU - Cichero, Elena

AU - Espinoza, Stefano

AU - Gainetdinov, Raul R.

AU - Brasili, Livio

AU - Fossa, Paola

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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 (T1AM). 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 β2-adrenoreceptor binding site, available by X-ray crystallization studies, and with the homology modelled 5HT1A receptor. The obtained results, in tandem with docking studies performed with RO5166017, β-PEA and T1AM, provided an opportunity to reasonably identify the hTAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists. The molecular mechanisms of interaction between the hTAAR1 and its agonists is explored by homology modeling and docking studies. Results provide an opportunity to identify the key residues involved in ligand recognition and to define important starting points to design new agonists.

AB - 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 (T1AM). 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 β2-adrenoreceptor binding site, available by X-ray crystallization studies, and with the homology modelled 5HT1A receptor. The obtained results, in tandem with docking studies performed with RO5166017, β-PEA and T1AM, provided an opportunity to reasonably identify the hTAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists. The molecular mechanisms of interaction between the hTAAR1 and its agonists is explored by homology modeling and docking studies. Results provide an opportunity to identify the key residues involved in ligand recognition and to define important starting points to design new agonists.

KW - GPCR

KW - Homology modelling

KW - Molecular docking

KW - TAAR1

KW - Trace amine-associated receptor

UR - http://www.scopus.com/inward/record.url?scp=84875644288&partnerID=8YFLogxK

U2 - 10.1111/cbdd.12018

DO - 10.1111/cbdd.12018

M3 - Article

C2 - 22883051

AN - SCOPUS:84875644288

VL - 81

SP - 509

EP - 516

JO - Chemical Biology and Drug Design

JF - Chemical Biology and Drug Design

SN - 1747-0277

IS - 4

ER -