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

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

Research output: Contribution to journalArticlepeer-review


Trace amine-associated receptors (TAARs) were discovered in 2001 as new members of class A G protein-coupled receptors (GPCRs). With the only exception of TAAR1, TAAR members (TAAR2-9, also known as noncanonical olfactory receptors) were originally described exclusively in the olfactory epithelium and believed to mediate the innate perception of volatile amines. However, most noncanonical olfactory receptors are still orphan receptors. Given its recently discovered nonolfactory expression and therapeutic potential, TAAR5 has been the focus of deorphanization campaigns that led to the discovery of a few druglike antagonists. Here, we report four novel TAAR5 antagonists identified through high-throughput screening, which, along with the four ligands published in the literature, constituted our starting point to design a computational strategy for the identification of TAAR5 ligands. We developed a structure-based virtual screening protocol that allowed us to identify three new TAAR5 antagonists with a hit rate of 10%. Despite lacking an experimental structure, we accurately modeled the TAAR5 binding site by integrating comparative sequence- and structure-based analyses of serotonin receptors with homology modeling and side-chain optimization. In summary, we have identified seven new TAAR5 antagonists that could serve as lead candidates for the development of new treatments for depression, anxiety, and neurodegenerative diseases.

Original languageEnglish
Pages (from-to)6667-6680
Number of pages14
JournalJournal of Chemical Information and Modeling
Issue number21
StatePublished - 13 Nov 2023


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