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

Journal of Chemical Information and Modeling, vol. 63, pp. 6667–6680

Abstract

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.

Authors 9

1. Alessandro Nicoli

   Leibniz-Institute for Food Systems Biology at the Technical University of Munich · Technical University of Munich

   Affiliation as printed

   Chemoinformatics and Protein Modelling, Department of Molecular Life Sciences, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany

   Leibniz Institute for Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany

2. Verena Weber Aachen Faculty of Mathematics, Computer Science and Natural Sciences

   Forschungszentrum Jülich · Leibniz-Institute for Food Systems Biology at the Technical University of Munich · RWTH Aachen University

   Affiliation as printed

   Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen, Aachen, 52062 Germany

   Institute for Advanced Simulations (IAS)-5/Institute for Neuroscience and Medicine (INM)-9, Forschungszentrum Jülich, 52428 Jülich, Germany

   Leibniz Institute for Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany

3. Carlotta Bon

   Italian Institute of Technology

   Affiliation as printed

   Istituto Italiano di Tecnologia, 16163 Genova, Italy

4. Alexandra Steuer

   Leibniz-Institute for Food Systems Biology at the Technical University of Munich · Technical University of Munich

   Affiliation as printed

   Chemoinformatics and Protein Modelling, Department of Molecular Life Sciences, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany

   Leibniz Institute for Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany

5. Stefano Gustincich

   Italian Institute of Technology

   Affiliation as printed

   Istituto Italiano di Tecnologia, 16163 Genova, Italy

6. Raul R. Gainetdinov

   St Petersburg University

   Affiliation as printed

   Institute of Translational Biomedicine and Saint Petersburg University Hospital, Saint Petersburg State University, Saint Petersburg 199034, Russia

7. Roman Lang

   Leibniz-Institute for Food Systems Biology at the Technical University of Munich

   Affiliation as printed

   Leibniz Institute for Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany

8. Stefano Espinoza corresponding

   Università degli Studi del Piemonte Orientale “Amedeo Avogadro” · Italian Institute of Technology

   Affiliation as printed

   Dipartimento di Scienze della Salute, Università del Piemonte Orientale, 28100 Novara, Italy

   Istituto Italiano di Tecnologia, 16163 Genova, Italy

9. Antonella Di Pizio corresponding

   Leibniz-Institute for Food Systems Biology at the Technical University of Munich · Technical University of Munich

   Affiliation as printed

   Chemoinformatics and Protein Modelling, Department of Molecular Life Sciences, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany

   Leibniz Institute for Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany