Accepted_test

The glucagon-like peptide-1 (GLP-1) hormone is pivotal in glucose regulation post-food intake, primarily through its interaction with the GLP-1 receptor (GLP-1R). This interaction triggers insulin release and inhibits glucagon secretion, influencing metabolic processes. Peptidic GLP-1R agonists, such as semaglutide and liraglutide, are approved for Type 2 Diabetes Mellitus (T2DM) treatment, although administration challenges exist. Thus, we explore alternative delivery methods, emphasizing oral administration for improved patient compliance. GLP-1R agonists also exhibit potential cardiovascular benefits, yet small molecule drug development poses challenges.

Assessing ligand-receptor interactions involves binding free energy analysis, traditionally resource-intensive. We used funnel metadynamics, a computational technique enhancing sampling efficiency. With this approach, we aim to investigate the binding free energy of small molecules with GLP-1R, validating our method's accuracy against known binding free energies.

Our study demonstrates close agreement between calculated and experimental binding free energy values, validating our approach. Moreover, we determine free binding energies for novel small molecules interacting with GLP-1R, offering insights into potential therapeutic candidates. Funnel metadynamics proves effective, suggesting its utility in identifying potential agonist molecules. Further exploration with funnel metadynamics may unveil complex molecular interactions, facilitating the development of more effective and specific drugs.