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.