title: Insights into the binding modes of human β₃-adrenergic receptor agonists with ligand-based and receptor-based methods.
abstract: Agonists of β(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 β(3)-AR agonists as well as to identify new lead compounds activating β(3)-AR, ligand-based and receptor-based methods were applied. The pharmacophore models were developed based on 144 β(3)-AR agonists. Meanwhile, the homology model of the β(3)-AR was built based on the crystal structure of β(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, π-π stacking interaction with residues Phe308, and hydrophobic interactions with residues Val118, Val121, Ala197, Phe198, Ala199, Phe309, and Phe328 of β(3)-AR. And the major difference about binding mode from the crystal structures of β(1)- and β(2)-ARs is the hydrogen-bonding interaction with the residue Arg315, which corresponds to the residue Asn313 of β(1)-AR and the residue His296 of β(2)-AR, respectively. Our findings may be crucial for the design and development of novel selective and potent β(3)-AR agonists.
authors.affiliation: School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Jin
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Xianqiang
authors.initials: X
authors.lastname: Sun
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Guixia
authors.initials: G
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D022702:Receptors, Adrenergic, beta-3 / Q000737:chemistry / Q000378:metabolism*; D015203:Reproducibility of Results; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D008024:Ligands; D022702:Receptors, Adrenergic, beta-3