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.

Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study

“…8,9 These findings were supported by further homology modeling and docking studies we performed within the murine and human TAAR1 and TAAR5 receptors with respect to T 1 AM ligand 10 and were also in accordance with the key role played by a proper basic feature included in any TAAR1 ligand, as reported in literature. 11 Notably, this information was definitively validated by the mutagenesis data involving the D102 residue, reported by Reese.…”

“…Docking studies were performed starting from the in-house homology model of the murine TAAR1 receptor, 4 built on the X-ray structure of the human β2-adrenoreceptor (PDB ID: 3PDS), 17 following a protocol we previously discussed exploring the binding mode of other TAAR1 ligands. 8,9 Briefly, the most promising compounds were docked into the putative ligand binding site by means of the Surflex docking module implemented in Sybyl-X1.0. 18 Surflex-Dock uses an empirically derived scoring function based on the binding affinities of X-ray protein−ligand complexes.…”

Evolutionary Conservation of 3-Iodothyronamine as an Agonist at the Trace Amine-Associated Receptor 1

“…Cichero et al [32] also revealed Asp102 (in human TAAR1 position 103) and Asn283 (in human TAAR1 position 286) as anchor points for the ligand recognition process. They suggested that T 1 AM is engaged in hydrogen bonds with Asn283 (in human TAAR1 position 286) and Asp284 (in human TAAR1 position 287) [32].…”

In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1

“…Sitedirected mutagenesis studies have identified two locations in TAAR1 transmembrane domains 6 and 7, where amino acid substitutions markedly reduce or increase methamphetamine TAAR1 activation potencies in the rat and mouse TAAR1 (Reese et al, 2014). Docking studies with a homology model for the human TAAR1 (Cichero et al, 2013(Cichero et al, , 2014 could serve to further elucidate the essential amino acids that are required for ligand binding and discover structural determinants for the TAAR1 activity or inactivity of psychoactive substances.…”