Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain...

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Published in:International journal of molecular sciences 2022-03, Vol.23 (6), p.3127
Main Authors: Bon, Carlotta, Chern, Ting-Rong, Cichero, Elena, O'Brien, Terrence E, Gustincich, Stefano, Gainetdinov, Raul R, Espinoza, Stefano
Format: Article
Language:English
Subjects:
antagonist
Antidepressants
AtomNet
Behavior
Brain
BRET
Cyclic AMP response element-binding protein
Deep learning
Dopamine
Drug dosages
Emotional behavior
Emotional disorders
Inhibition (psychology)
Ligands
Mental depression
Methylamine
Mood disorders
Neural networks
Neural Networks, Computer
Neurogenesis
Olfactory epithelium
Olfactory Mucosa
Pharmacokinetics
Phosphorylation
Proteins
Receptors, G-Protein-Coupled
Serotonin
Signal Transduction
trace amine-associated receptor 5
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Summary:Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to further develop more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23063127