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

Abstract

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.

Novel fatty chain-modified GLP-1R G-protein biased agonist exerts prolonged anti-diabetic effects through targeting receptor binding sites

“…The pharmacokinetic proles of PX17 were studied in male cynomolgus monkeys (0.1 and 0.3 mg kg À1 , n ¼ 4) aer a subcutaneous injection. Blood samples were collected at predose, 1,6,12,24,36,48,72,96,144,192 and 240 h. Plasma concentrations of PX17 were determined by a liquid chromatography-mass spectrometry (LC-MS) method. Assay sensitivity was estimated to be 10 ng mL À1 and detection range was between 20-3000 ng mL À1 .…”

“…[8][9][10] Among these incretins, GLP-1 and its analogs, as the external GLP-1R agonists have been intensively developed. 11,12 GLP-1, as an endogenous peptide hormone comprising 30-amino-acids, was secreted in response to food ingestion in gut L-cells. The secreted GLP-1 plays important roles in glucose homeostasis in a glucose-dependent model without hypoglycemic risk.…”

Bayesian metamodeling of complex biological systems across varying representations

“…The shaded areas indicate standard deviation in the posterior PDFs. (C) Metamodeled time courses are shown for postprandial response with and without a GLP1R agonist in the virtual screening model, using analogue M2 in the virtual screening library (93). (D) Experimental time courses are shown for postprandial response with and without a GLP1R agonist, exenatide (synthetic Exendin-4) (23).…”

“…The model is based on computational docking of 5,689 potential agonists against an atomic structure of GLP1R (93). These potential agonists were ranked by their predicted affinity to the allosteric site of GLP1R.…”

Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist S6 Stimulates Insulin Secretion From Rat Islets

“…However, they are peptides that require administration via subcutaneous injection, and concerns regarding their compliance for long-term use have emerged ( Elashoff et al, 2011 ). To our knowledge, no small molecule agents acting as GLP-1R agonists are available for clinical use ( Redij et al, 2019 ). Hence, the development of small molecule drugs suitable for oral administration that target GLP-1R would be appropriate to circumvent this problem.…”