Structural review of protein-ligand interactions for six key cardiometabolic drug targets (GLP-1R, GIPR, FGFR1/β-Klotho, PCSK9, NF-κB, NLRP3), analyzing binding domain architecture and mechanisms that govern tirzepatide's dual GLP-1R/GIPR engagement and its cardiometabolic superiority. Uses curated structural datasets to map interaction mechanisms. Provides drug development-focused structural insights into tirzepatide's dual receptor binding—informing the rational design of next-generation multi-receptor agonists and explaining the molecular basis for tirzepatide's superior cardiometabolic outcomes relative to monoagonist GLP-1 RAs.
Abstract
Cardiometabolic diseases (CVDs) are the leading cause of premature mortality and disability worldwide, arising from of cardiovascular and metabolic dysregulation. This review focuses on six critical therapeutic targets established in cardiometabolic regulation: GLP-1R, GIPR, FGFR1/β-Klotho, PCSK9, NF-κB, and the NLRP3 inflammasome. Drawing on curated structural datasets, we analyze the mechanisms of action and map key binding domain features that govern ligand efficacy and specificity. Dual GLP-1R/GIPR agonists, such as tirzepatide, demonstrate superior outcomes in glycemic control and weight reduction. Concurrently, inhibiting PCSK9, NF-κB, and NLRP3 helps to lower cholesterol and reduce harmful inflammation, offering cardioprotection. Structural analysis across these targets reveals complementary motifs (aromatic, hydrophobic, and polar residues). These insights guide the rational design of next-generation multi-target ligands (molecules capable of modulating two or more biological targets involved in related disease pathways, producing integrated therapeutic effects). Such integrated agents are promising for providing combined cardiovascular and metabolic benefits, thus reducing the risks associated with complex therapeutic drug combinations.