Insights into the binding modes of human β3-adrenergic receptor agonists with ligand-based and receptor-based methods

Agonists of beta(3)-adrenergic receptor (AR) have been thought as potential drugs for the treatment of obesity, type II diabetes, and overactive bladder. In order to clarify the essential structure-activity relationship and the detailed binding modes of beta(3)-AR agonists as well as to identify new lead compounds activating beta(3)-AR, ligand-based and receptor-based methods were applied. The pharmacophoremodels were developed based on 144 beta(3)-AR agonists. Meanwhile, the homology model of the beta(3)-AR was built based on the crystal structure of beta(2)-AR. The pharmacophore model and the homology model mapped with each other very well, and some important information was obtained from the docking result. For example, agonists formed similar hydrogen-bonding interactions with residues Asp117, Arg315, and Asn332, pi-pi stacking interaction with residues Phe308, and hydrophobic interactions with residues Val118, Val121, Ala197, Phe198, Ala199, Phe309, and Phe328 of beta(3)-AR. And the major difference about binding mode from the crystal structures of beta(1)- and beta(2)-ARs is the hydrogen-bonding interaction with the residue Arg315, which corresponds to the residue Asn313 of beta(1)-AR and the residue His296 of beta(2)-AR, respectively. Our findings may be crucial for the design and development of novel selective and potent beta(3)-AR agonists.