TY - JOUR

T1 - Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

AU - Bon, Carlotta

AU - Chern, Ting-Rong

AU - Cichero, Elena

AU - E. O’Brien, Terrence

AU - Gustincich, Stefano

AU - Gainetdinov , Raul R.

AU - Espinoza, Stefano

N1 - 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. https://doi.org/10.3390/ijms23063127

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - trace amine-associated receptor 5

KW - antagonist

KW - AtomNet

KW - BRET

U2 - 10.3390/ijms23063127

DO - 10.3390/ijms23063127

M3 - Article

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 6

M1 - 3127

ER -