Discovery of a Novel Chemo-Type for TAAR1 Agonism via Molecular Modeling

The search for novel effective TAAR1 ligands continues to draw great attention due to the wide range of pharmacological applications related to TAAR1 targeting. Herein, molecular docking studies of known TAAR1 ligands, characterized by an oxazoline core, have been performed in order to identify nove...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2024-04, Vol.29 (8), p.1739
Main Authors: Grossi, Giancarlo, Scarano, Naomi, Musumeci, Francesca, Tonelli, Michele, Kanov, Evgeny, Carbone, Anna, Fossa, Paola, Gainetdinov, Raul R, Cichero, Elena, Schenone, Silvia
Format: Article
Language:English
Subjects:
agonist
AlphaFold
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Binding Sites
Cancer
Catecholamines
Chemotherapy
Computer software industry
Drug Discovery
Humans
Investigations
Ligands
Models, Molecular
molecular docking
Molecular Docking Simulation
Molecular Structure
Oxazoles - chemistry
Oxazoles - pharmacology
Protein Binding
Proteins
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - chemistry
Receptors, G-Protein-Coupled - metabolism
Schizophrenia
Software
Structure-Activity Relationship
TAAR1
trace amine receptor
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Summary:The search for novel effective TAAR1 ligands continues to draw great attention due to the wide range of pharmacological applications related to TAAR1 targeting. Herein, molecular docking studies of known TAAR1 ligands, characterized by an oxazoline core, have been performed in order to identify novel promising chemo-types for the discovery of more active TAAR1 agonists. In particular, the oxazoline-based compound has been taken as a reference compound for the computational study, leading to the development of quite flat and conformationally locked ligands. The choice of a "Y-shape" conformation was suggested for the design of TAAR1 ligands, interacting with the protein cavity delimited by ASP103 and aromatic residues such as PHE186, PHE195, PHE268, and PHE267. The obtained results allowed us to preliminary in silico screen an in-house series of pyrimidinone-benzimidazoles ( - ) as a novel scaffold to target TAAR1. Combined ligand-based (LBCM) and structure based (SBCM) computational methods suggested the biological evaluation of compounds - , leading to the identification of derivatives - (hTAAR1 EC = 526.3-657.4 nM) as promising novel TAAR1 agonists.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules29081739