Structure-Based Discovery of Mouse Trace Amine-Associated Receptor 5 Antagonists

Nicoli, Alessandro; Weber, Verena; Bon, Carlotta; Steuer, Alexandra; Gustincich, Stefano; Gainetdinov, Raul R.; Lang, Roman; Espinoza, Stefano; Di Pizio, Antonella

doi:10.1021/acs.jcim.3c00755

Cited by 3 publications

(2 citation statements)

References 104 publications

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“…In 2022, the Atomwise AtomNet ® convolutional neural network virtual screening technology was utilized to select a chemically diverse set of 94 predicted hits, of which 2 antagonists with low micromolar potency were identified for a 2% hit rate [265]. In 2023, a virtual screening protocol that included both pharmacophore filtering and docking was used to identify TAAR5 antagonists with a 10% hit rate [266]. Relative to these studies, the machine classifier developed in this study is very promising as a virtual screening tool.…”

Section: Discussionmentioning

confidence: 99%

G Protein-Coupled Receptor–Ligand Pose and Functional Class Prediction

Szwabowski,

Griffing,

Mugabe

et al. 2024

IJMS

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G protein-coupled receptor (GPCR) transmembrane protein family members play essential roles in physiology. Numerous pharmaceuticals target GPCRs, and many drug discovery programs utilize virtual screening (VS) against GPCR targets. Improvements in the accuracy of predicting new molecules that bind to and either activate or inhibit GPCR function would accelerate such drug discovery programs. This work addresses two significant research questions. First, do ligand interaction fingerprints provide a substantial advantage over automated methods of binding site selection for classical docking? Second, can the functional status of prospective screening candidates be predicted from ligand interaction fingerprints using a random forest classifier? Ligand interaction fingerprints were found to offer modest advantages in sampling accurate poses, but no substantial advantage in the final set of top-ranked poses after scoring, and, thus, were not used in the generation of the ligand–receptor complexes used to train and test the random forest classifier. A binary classifier which treated agonists, antagonists, and inverse agonists as active and all other ligands as inactive proved highly effective in ligand function prediction in an external test set of GPR31 and TAAR2 candidate ligands with a hit rate of 82.6% actual actives within the set of predicted actives.

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Section: Discussionmentioning

confidence: 99%

G Protein-Coupled Receptor–Ligand Pose and Functional Class Prediction

Szwabowski,

Griffing,

Mugabe

et al. 2024

IJMS

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“…Such consequences of the absence of TAARs suggest the antidepressant potential of their antagonists. The search for such TAAR5 antagonists has already started [ 120 ].…”

Section: The Family Of Taars—a New Target For Depression Therapy?mentioning

confidence: 99%

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

Shemiakova,

Efimova,

Gainetdinov

2024

Biomedicines

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Depression is a common mental illness of great concern. Current therapy for depression is only suitable for 80% of patients and is often associated with unwanted side effects. In this regard, the search for and development of new antidepressant agents remains an urgent task. In this review, we discuss the current available evidence indicating that G protein-coupled trace amine-associated receptors (TAARs) might represent new targets for depression treatment. The most frequently studied receptor TAAR1 has already been investigated in the treatment of schizophrenia, demonstrating antidepressant and anxiolytic properties. In fact, the TAAR1 agonist Ulotaront is currently undergoing phase 2/3 clinical trials testing its safety and efficacy in the treatment of major depressive disorder and generalized anxiety disorder. Other members of the TAAR family (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) are not only involved in the innate olfaction of volatile amines, but are also expressed in the limbic brain areas. Furthermore, animal studies have shown that TAAR2 and TAAR5 regulate emotional behaviors and thus may hold promise as potential antidepressant targets. Of particular interest is their connection with the dopamine and serotonin systems of the brain and their involvement in the regulation of adult neurogenesis, known to be affected by the antidepressant drugs currently in use. Further non-clinical and clinical studies are necessary to validate TAAR1 (and potentially other TAARs) as novel therapeutic targets for the treatment of depression.

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Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands

Scarano,

Espinoza,

Brullo

et al. 2024

IJMS

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G-protein-coupled receptors (GPCRs) represent a family of druggable targets when treating several diseases and continue to be a leading part of the drug discovery process. Trace amine-associated receptors (TAARs) are GPCRs involved in many physiological functions with TAAR1 having important roles within the central nervous system (CNS). By using homology modeling methods, the responsiveness of TAAR1 to endogenous and synthetic ligands has been explored. In addition, the discovery of different chemo-types as selective murine and/or human TAAR1 ligands has helped in the understanding of the species-specificity preferences. The availability of TAAR1–ligand complexes sheds light on how different ligands bind TAAR1. TAAR5 is considered an olfactory receptor but has specific involvement in some brain functions. In this case, the drug discovery effort has been limited. Here, we review the successful computational efforts developed in the search for novel TAAR1 and TAAR5 ligands. A specific focus on applying structure-based and/or ligand-based methods has been done. We also give a perspective of the experimental data available to guide the future drug design of new ligands, probing species-specificity preferences towards more selective ligands. Hints for applying repositioning approaches are also discussed.

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Structure-Based Discovery of Mouse Trace Amine-Associated Receptor 5 Antagonists

Cited by 3 publications

References 104 publications

G Protein-Coupled Receptor–Ligand Pose and Functional Class Prediction

G Protein-Coupled Receptor–Ligand Pose and Functional Class Prediction

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands

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