Glucagon-like peptide-1 receptor (GLP-1R) found on β-cells of the pancreas involves in control of blood sugar levels by enhancing insulin secretion. In patients with type 2 diabetes, the peptide hormone glucagon-like peptide (GLP)-1 has necessary actions that result in glucose-lowering and weight loss. But being a peptide hormone, it must be injected which makes it difficult for the administration. Peptides drugs have been used for GLP-1 receptors as an agonist to treat type-2 diabetes, but when taken orally they have low bioavailability, low stability, shorter half-life, and their high production cost makes its usage limited. Therefore, there is a necessity to identify and develop a small molecule agonist that binds and activates the receptor. PF-06882961 is a potent, orally bioavailable small molecule agonist of GLP-1 receptor under phase 2 clinical trial. In the present study, we used crystal structure PF-06882961 bound to GLP-1 receptor (PDB ID: 6X1A) for molecular docking of drugs by using virtual screening to analyze the binding affinity of the potential compounds. A total of 17 million zinc15 compounds were screened, and the potential hits were recognized based on their docking score and ligand-protein interaction. Twenty top compounds were identified as the best compounds using the glide XP docking which then underwent MD simulation (200 ns) to be further validated as a potential drug target. Encouragingly, six of the compounds showed stable binding reactions after using MD simulation. Our computational pipeline methods suggest that the resulting top six compounds could potentially be the small-molecule agonist for the GLP-1 receptor.

High throughput virtual screening to identify small molecule agonists for glucagon-like peptide-1 receptor

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.