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.

The essential role for aromatic cluster in the β3 adrenergic receptor

“…The predicted binding mode demonstrated that both F308 6.51 and F309 6.52 were located in the binding pocket and that they had hydrophobic interactions with BRL ( Figure 3A), which are consistent with our results and the newly reported observations [36] . However, through the homology and molecular docking studies, we could not conclude that F309…”

In vitro Antioxidant Properties of Novel ?3-Adrenoceptor Agonists Bearing Benzenesulfonamide Fragment

“…The design of potent, selective human β 3 -AR agonists has been traditionally focused on the compounds in which aryloxypropanolamine or arylethanolamine pharmacophore has been attached to substituted (hetero)aryl fragment through ethane-1,2-diyl spacer. 17,18 Additionally, in terms of identification of the essential features for β 3 -AR agonistic activity has been previously observed, that the free secondary amino and hydroxyl groups within such molecules have been regarded as essential structural requirements. 19 An insight into chemical structure of currently investigated aryloxypropanolamine-based compounds BL-14S2-BL-44S2 ( Table 1) has revealed that they have met the criteria mentioned above.…”

Pharmacophore‐guided Virtual Screening to Identify New β3‐adrenergic Receptor Agonists

“…Jin model [30] 144 (35, 109) H, PI, RA, H, HBA Catalyst v4.10 Saxena-Roy model [31] 175 (51, 124) HBD, PI, H, NI, H Discovery Studio v2.0 Ujiantari model 95 (19,76) H, HBD, HBA, HBD, PI, H LigandScout v3.12 [a] HBD: hydrogen bond donor, HBA: hydrogen bond acceptor, PI: positive ionizable, NI: negative ionizable, H: hydrophobic interaction, RA: ring aromatic, HpAI: hydrophobic aliphatic, HpAr: hydrophobic aromatic. [b] The model was used in the virtual screening process, but without biological testing of hits.…”

“…However, none of those studies involved experimental in vitro validation of predicted hits. [27][28][29][30][31] Therefore, this study aimed to perform pharmacophore-based virtual screening and also confirm the biological activity of selected hit compounds.…”