Pharmacophore-guided Virtual Screening to Identify New beta(3)-adrenergic Receptor Agonists

The beta(3)-adrenergic receptor (beta(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 beta(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 beta(3)-AR agonists are needed as staffing points for drug development. Previous pharmacophore modeling studies of the beta(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. Ligarid-based pharmacophore modeling was performed since no 3D structure of human beta(3)-AR is yet available. A dataset consisting of beta(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 beta(3)-AR. Out of 35 tested compounds, 4 compounds were active in CHO-K1 cells expressing the human beta(3)-AR, and 8 compounds were active in CHO-K1 cells expressing the mouse beta(3)-AR.