<br/>The activation of glucagon-like peptide 1 receptor (GLP-1R) is responsible for the management of glucose levels in the body and a defect can lead to type II diabetes. We investigate GLP-1R and a potential novel drug that is used to activate GLP-1R using computational modeling. The novel drug is believed to be a positive allosteric modulator and acts as an agonist (ago-PAM).<br/>We have created a homology model of the C-terminal transmembrane (TMD) and N-terminal extracellular domain (ECD) model based on the cryo-EM data of the full sequence of GLP-1R (PDBID:5VAI). These two domains are believed to be involved in the binding mechanism of GLP-1R and its native peptide, glucagon-like peptide 1 (GLP-1). Since we plan on performing simulations that included GLP-1, the domains were connected with a linker and loop refinement was performed to obtain our initial structure.<br/>Molecular dynamics (MD) was carried out with GLP-1R within a phosphatidylcholine (POPC) bilayer membrane, and water environment. Multiple simulations were carried out with GLP-1R and GLP-1, GLP-1R and the novel drug, and GLP-1R with the novel drug and GLP-1.We assessed the stability of the structures with RMSD measurements and will determine the binding energies of the novel drug. In addition, we will perform per-residue RMSD to determine which residues may be active when binding occurs and the docked poses will also be obtained.<br/>With these results, we should be able to determine if the novel drug is effective when compared with other existing drugs. If so, this compound may prove to be a viable new treatment for patients with diabetes that merits further evaluation. This will also support the idea that developing small-molecule agonists that act allosterically is a pathway that should be explored further in addition to the traditional peptide-based drugs.

Computational modeling of GLP-1R and novel small-molecule allosteric agonist for type II diabetes

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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