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.