Computational assessment of the dimeric incretin GLP-1cpGLP-1 reveals the structural bases for its activity

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired insulin secretion, leading to hyperglycemia. The glucagon-like peptide-1 receptor (GLP-1R), a class B1 G protein-coupled receptor (GPCR), plays a crucial role in glucose homeostasis by enhancing insulin secretion, inhibiting glucagon release, and promoting satiety. However, the short half-life of endogenous GLP-1 due to rapid enzymatic degradation has led to the development of GLP-1 receptor agonists (GLP-1RAs) with improved stability and efficacy. This study investigates GLP-1cpGLP-1, a dimeric GLP-1 analog active in vivo, incorporating a flexible C-peptide linker, designed to enhance receptor activation and prolong therapeutic effects. Using molecular dynamics simulations and structural modeling, we analyzed the interaction dynamics of GLP-1cpGLP-1 with GLP-1R, comparing its binding mode to native GLP-1. Our findings reveal that GLP-1cpGLP-1 maintains essential interactions required for receptor activation while introducing novel contacts at an allosteric site, suggesting a possible positive allosteric auto-modulation mechanism. These insights highlight GLP-1cpGLP-1's potential as an innovative GLP-1RA with enhanced pharmacokinetics and receptor engagement, paving the way for future incretin-based therapeutics in T2DM and obesity.