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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.

Structural Modeling and in Silico Screening of Potential Small-Molecule Allosteric Agonists of a Glucagon-like Peptide 1 Receptor