Pharmacophore‐guided Virtual Screening to Identify New β(3)‐adrenergic Receptor Agonists

The β(3)‐adrenergic receptor (β(3)‐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 β(3)‐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 β(3)‐AR agonists are needed as starting points for drug development. Previous pharmacophore modeling studies of the β(3)‐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 β(3)‐AR is yet available. A dataset consisting of β(3)‐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 β(3)‐AR. Out of 35 tested compounds, 4 compounds were active in CHO−K1 cells expressing the human β(3)‐AR, and 8 compounds were active in CHO−K1 cells expressing the mouse β(3)‐AR.