10.1021/acsomega.8b03052.s001
Tejashree Redij
Tejashree
Redij
Rajan Chaudhari
Rajan
Chaudhari
Zhiyu Li
Zhiyu
Li
Xianxin Hua
Xianxin
Hua
Zhijun Li
Zhijun
Li
Structural Modeling and in Silico Screening of Potential
Small-Molecule Allosteric Agonists of a Glucagon-like Peptide 1 Receptor
American Chemical Society
2019
class B GPCRs
Potential Small-Molecule Allosteric Agonists
compound
GLP -1R agonists
small-molecule drug discovery
class B family
incretin peptide ligand GLP
type 2 diabetes
glucagon-like peptide 1 receptor
Glucagon-like Peptide 1 Receptor
cAMP response element-based luciferase
TM
nonpeptidic small-molecule drugs
GLP -1R
allosteric binding site
2019-01-11 09:14:12
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Structural_Modeling_and_in_Silico_Screening_of_Potential_Small-Molecule_Allosteric_Agonists_of_a_Glucagon-like_Peptide_1_Receptor/7577606
The
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.