Insights into β-adrenoceptor agonism through comprehensive investigation.

Research onβ 3 -AR, the new member of the adrenoceptor family, is in its infancy and few β 3 -AR agonists have been approved for marketing to date. Meanwhile, β 3 -AR exhibited obvious species differences in pharmacological properties, such as between human and animals, however, the 3D structure of human β 3 -AR has not been published, which makes it difficult to understand the interaction between human β 3 -AR and its agonists. Herein, binding patterns of β 3 -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 3 -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 3 -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 3 -AR and its agonists. Display Omitted • The binding patterns of β 3 -AR agonists are explored starting from the Alphafold predicted structural model followed by refinement through molecular dynamics simulation. • Through multiple integrated computational approaches, the features of the β 3 -AR active pocket and the structure-activity relationship of the agonists were elucidated to provide theoretical guidance for the rational design of human β 3 -AR agonists.