ao8b03052_si_001.pdf (1.64 MB)
Structural Modeling and in Silico Screening of Potential Small-Molecule Allosteric Agonists of a Glucagon-like Peptide 1 Receptor
journal contribution
posted on 2019-01-11, 09:14 authored by Tejashree Redij, Rajan Chaudhari, Zhiyu Li, Xianxin Hua, Zhijun LiThe
glucagon-like peptide 1 receptor (GLP-1R) belongs to the pharmaceutically
important class B family of G-protein-coupled receptors (GPCRs), and
its incretin peptide ligand GLP-1 analogs are adopted drugs for the
treatment of type 2 diabetes. Despite remarkable antidiabetic effects,
GLP-1 peptide-based drugs are limited by the need of injection. On
the other hand, developing nonpeptidic small-molecule drugs targeting
GLP-1R remains elusive. Here, we first constructed a three-dimensional
structure model of the transmembrane (TM) domain of human GLP-1R using
homology modeling and conformational sampling techniques. Next, a
potential allosteric binding site on the TM domain was predicted computationally.
In silico screening of druglike compounds against this predicted allosteric
site has identified nine compounds as potential GLP-1R agonists. The
independent agonistic activity of two compounds was subsequently confirmed
using a cAMP response element-based luciferase reporting system. One
compound was also shown to stimulate insulin secretion through in
vitro assay. In addition, this compound synergized with GLP-1 to activate
human GLP-1R. These results demonstrated that allosteric regulation
potentially exists in GLP-1R and can be exploited for developing small-molecule
agonists. The success of this work will help pave the way for small-molecule
drug discovery targeting other class B GPCRs through allosteric regulations.
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class B GPCRsPotential Small-Molecule Allosteric AgonistscompoundGLP -1R agonistssmall-molecule drug discoveryclass B familyincretin peptide ligand GLPtype 2 diabetesglucagon-like peptide 1 receptorGlucagon-like Peptide 1 ReceptorcAMP response element-based luciferaseTMnonpeptidic small-molecule drugsGLP -1Rallosteric binding site
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