Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 5 February 2022 / Approved: 7 February 2022 / Online: 7 February 2022 (11:57:16 CET)

A peer-reviewed article of this Preprint also exists.

Bon, C.; Chern, T.-R.; Cichero, E.; O’Brien, T.E.; Gustincich, S.; Gainetdinov, R.R.; Espinoza, S. Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network. Int. J. Mol. Sci. 2022, 23, 3127. Bon, C.; Chern, T.-R.; Cichero, E.; O’Brien, T.E.; Gustincich, S.; Gainetdinov, R.R.; Espinoza, S. Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network. Int. J. Mol. Sci. 2022, 23, 3127.

Journal reference: Int. J. Mol. Sci. 2022, 23, 3127
DOI: 10.3390/ijms23063127

Abstract

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 develop further more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.

Keywords

Trace amine-associated receptor 5; antagonist; AtomNet; BRET.

Subject

BIOLOGY, Other

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