Pharmacophore-guided Virtual Screening to Identify New β3-adrenergic Receptor Agonists

The β3-adrenergic receptor (β3-AR) is found in several tissues such as adipose tissue and urinary bladder. It is a therapeutic target because it plays a role in thermogenesis, lipolysis, and bladder relaxation. Two β3-AR agonists are used clinically: mirabegron 1 and vibegron 2, which are indicated for overactive bladder syndrome. However, these drugs show adverse effects, including increased blood pressure in mirabegron patients. Hence, new β3-AR agonists are needed as starting points for drug development. Previous pharmacophore modeling studies of the β3-AR did not involve experimental in vitro validation. Therefore, this study aimed to conduct prospective virtual screening and confirm the biological activity of virtual hits. Ligand-based pharmacophore modeling was performed since no 3D structure of human β3-AR is yet available. A dataset consisting of β3-AR agonists was prepared to build and validate the pharmacophore models. The best model was employed for prospective virtual screening, followed by physicochemical property filtering and a docking evaluation. To confirm the activity of the virtual hits, an in vitro assay was conducted, measuring cAMP levels at the cloned β3-AR. Out of 35 tested compounds, 4 compounds were active in CHO−K1 cells expressing the human β3-AR, and 8 compounds were active in CHO−K1 cells expressing the mouse β3-AR. © 2022 The Authors. Molecular Informatics published by Wiley-VCH GmbH