Insights into β-adrenoceptor agonism through comprehensive in silico investigation.

Research onβ-AR, the new member of the adrenoceptor family, is in its infancy and few β-AR agonists have been approved for marketing to date. Meanwhile, β-AR exhibited obvious species differences in pharmacological properties, such as between human and animals, however, the 3D structure of human β-AR has not been published, which makes it difficult to understand the interaction between human β-AR and its agonists. Herein, binding patterns of β-AR agonists are explored starting from the Alphafold predicted structural model, and the obtained model was optimized by using molecular dynamics simulations. Moreover, the human β-AR and its agonists were subjected to molecular docking, dynamics simulations, binding free energy calculations and pharmacophore modeling to elucidate the characteristics of human β-AR activity pockets and agonist conformational relationships, including a hydrophobic group, a positively charged group as well as two hydrogen-bonded donors, which provide comprehensive insights into the interactions between human β-AR and its agonists.