Exploring GLP-1 peptide bound to its receptor, GLP-1R, through MD simulations and MMGBSA: Implications for rational drug design

Glucagon-like peptide-1(GLP-1) is a natural hormone that plays a key role in the pathophysiology of metabolic diseases, especially obesity and type 2 diabetes. However, GLP-1 is quickly broken down by enzymatic degradation, which leads to a short half-life and reduces its biological effectiveness. In view of this short half-life, we investigated the binding of GLP-1 to its receptor, GLP-1R, for the rational design of novel longer-acting peptide analogues. Results: The increasing prevalence of type 2 diabetes is a critical issue in health care. MD simulation, post-MD analyses and MM/GBSA approach were found promising to reveal detailed binding affinities of GLP-1 to GLP-1R. Our analyses suggested that the presence of GLP-1lowers GLP-1R stability, flexibility and also leads to strong positive correlations in the residual motions. MM/GBSA results show that the highest total binding energy was from a positively charged residue in the case of GLP-1R and a negatively charged residue in the case of GLP-1. Hence, we believe it is important to consider MM/GBSA results in the co nstruction of future novel peptide analogues . These findings potentially enhance the discovery and design of stable and efficacious peptide analogues.