Towards New Antidiabetic Development: Molecular Interactions Unfold Potential Agonistic Mechanisms of Naturally Occurring Terpenoids Against Structural Landscape of Glucagon-like Peptide-1 Receptor

Glucagon-like peptide-1 receptor (GLP-1R) is a focal target in antidiabetic drug discovery. Synthetic non-peptide compounds are routinely employed to investigate GLP-1R, however, scaffolds from natural products will offer us unique structural diversity to design more potent compounds. We investigated the potential of some natural compounds as agonists of GLP-1R. First, we carried out a virtual screening of 244 compounds, from 19 medicinal plants used in antidiabetic traditional medicine, against GLP-1R. We used molecular dynamics simulations, for 200ns, to further investigate the lead five compounds. Binding Free Energies (BFE), Root Mean Square Deviation (RMSD) and other parameters were employed to understand these interactions. Our results showed that lupeol (-57.23) had good BFE (kcal/mol) compared to danuglipron (-56.47), thus demonstrating more robust interactions with GLP-1R. The pocket-buried residues, CYS191 and GLN186, showed strong hydrogen bonds while the critical residue, TRP4, showed strong van der Waals interactions to stabilize the ligands. Moreover, the average RMSD (Å) of lupeol-bound GLP-1R (3.45) are comparable to danuglipron-bound GLP-1R (3.33), indicating good stability in the pocket. This potentially situates lupeol as GLP-1R agonist similar to danuglipron, and thus opens up the opportunity for more further experimental work, to validate its agonist properties on GLP1R.