TY - JOUR

T1 - A homology modelling-driven study leading to the discovery of the first mouse trace amine-associated receptor 5 (TAAR5) antagonists

AU - Cichero, Elena

AU - Espinoza, Stefano

AU - Tonelli, Michele

AU - Franchini, Silvia

AU - Gerasimov, Andrey S.

AU - Sorbi, Claudia

AU - Gainetdinov, Raul R.

AU - Brasili, Livio

AU - Fossa, Paola

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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, mTAAR5 and hTAAR5 homology models were built, in order to explore any pattern of structural requirements which could be involved in species-specific differences. Successively, the mTAAR5 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 mTAAR5 antagonists.

AB - 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, mTAAR5 and hTAAR5 homology models were built, in order to explore any pattern of structural requirements which could be involved in species-specific differences. Successively, the mTAAR5 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 mTAAR5 antagonists.

UR - http://www.scopus.com/inward/record.url?scp=84958966582&partnerID=8YFLogxK

U2 - 10.1039/c5md00490j

DO - 10.1039/c5md00490j

M3 - Article

AN - SCOPUS:84958966582

VL - 7

SP - 353

EP - 364

JO - MedChemComm

JF - MedChemComm

SN - 2040-2503

IS - 2

ER -