Discovery of a Novel Chemo-Type for TAAR1 Agonism via Molecular Modeling
Giancarlo Grossi,
Naomi Scarano,
Francesca Musumeci,
Michele Tonelli,
Evgeny Kanov,
Anna Carbone,
Paola Fossa,
Raul R. Gainetdinov,
Elena Cichero,
Silvia Schenone
Affiliations
Giancarlo Grossi
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
Naomi Scarano
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
Francesca Musumeci
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
Michele Tonelli
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
Evgeny Kanov
Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia
Anna Carbone
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
Paola Fossa
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
Raul R. Gainetdinov
Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia
Elena Cichero
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
Silvia Schenone
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
The search for novel effective TAAR1 ligands continues to draw great attention due to the wide range of pharmacological applications related to TAAR1 targeting. Herein, molecular docking studies of known TAAR1 ligands, characterized by an oxazoline core, have been performed in order to identify novel promising chemo-types for the discovery of more active TAAR1 agonists. In particular, the oxazoline-based compound S18616 has been taken as a reference compound for the computational study, leading to the development of quite flat and conformationally locked ligands. The choice of a “Y-shape” conformation was suggested for the design of TAAR1 ligands, interacting with the protein cavity delimited by ASP103 and aromatic residues such as PHE186, PHE195, PHE268, and PHE267. The obtained results allowed us to preliminary in silico screen an in-house series of pyrimidinone-benzimidazoles (1a–10a) as a novel scaffold to target TAAR1. Combined ligand-based (LBCM) and structure based (SBCM) computational methods suggested the biological evaluation of compounds 1a–10a, leading to the identification of derivatives 1a–3a (hTAAR1 EC50 = 526.3–657.4 nM) as promising novel TAAR1 agonists.
