The adrenergic receptors (ARs), member of the G protein-coupled receptors (GPCRs), are known as drug targets. β3-Adrenergic receptors (β3-ARs), the most recently discovered member of β-ARs, were found in several human tissues such as adipose tissue, urinary bladder, and blood vessels. Only two β3-AR agonists are available for clinical treatment such as mirabegron and vibegron indicated for overactive bladder (OAB), however, these drugs were shown to clinically increase blood pressure. Therefore, new β3-AR agonists are needed as starting points for drug development. Previous pharmacophore modeling studies did not involve experimental in vitro validation. Therefore, this study also included prospective virtual screening and confirmation of biological activity of selected hits. Ligand-based pharmacophore modeling was performed since no crystal structure of human β3-AR is yet available. A dataset consisting of 95 β3-AR agonists was prepared to build the pharmacophore models. The best model was employed for the prospective virtual screening, followed by physicochemical properties filtering and a docking evaluation. To confirm the activity of the candidate compounds, an in vitro assay was performed. Out of 35 tested compounds, four compounds were found to be active in CHO-hβ3AR cells and eight compounds were active in CHO-mβ3AR cells. The most active compound, Nav16 (Figure 1) increased the cAMP level with pEC50s of 4.89 ± 0.15 M in CHO-hβ3AR cells and 5.47 ± 0.43 M in CHO-mβ3AR cells, respectively.

Ligand-based pharmacophore modeling and virtual screening for discovery β3-adrenergic receptor agonists

ACS Spring Meeting 2021

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