A homology modelling-driven study leading to the discovery of the first mouse trace amine-associated receptor 5 (TAAR5) antagonists

• Published in: MedChemComm 2016-01, Vol.7 (2), p.353-364
• Main Authors: Cichero, Elena, Espinoza, Stefano, Tonelli, Michele, Franchini, Silvia, Gerasimov, Andrey S, Sorbi, Claudia, Gainetdinov, Raul R, Brasili, Livio, Fossa, Paola
• Format: Article
• Language: English
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c5md00490j

Several recent studies have focused on a detailed analysis of the trace amine-associated receptor type 5 (TAAR5) pharmacology, up to now revealing only a limited number of species-specific ligands, which are also active towards other TAAR receptors. In this context, we developed our work on TAAR5 applying a structure-based computational protocol, revolving around homology modeling and virtual screening calculations. In detail, m TAAR5 and h TAAR5 homology models were built, in order to explore any pattern of structural requirements which could be involved in species-specific differences. Successively, the m TAAR5 model was employed to perform a virtual screening of an in-house library of compounds, including different five-membered ring derivatives, linked to a phenyl ring through a flexible or a rigid basic moiety. The computational protocol applied allowed to select a number of chemical scaffolds that were tested in a biological assay leading to the discovery of the first two m TAAR5 antagonists. The computational study here proposed allowed us to discovery for the first time two TAAR5 antagonist, selective over the TAAR1 receptor.