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Protein-Ligand Interactions in Cardiometabolic Drug Targets: Focus on Weight Loss and Cardioprotection
Errikos Petsas1, Despoina P Kiouri1, Nikitas Georgiou1,2
1Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 11571 Athens, Greece.
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.
Insights
New multi-target drugs show promise for treating cardiometabolic diseases by simultaneously addressing blood sugar, weight, cholesterol, and inflammation. These integrated therapies aim to improve cardiovascular and metabolic health and reduce combination drug risks.
Area of Science:
- Pharmacology
- Molecular Biology
- Cardiology
Background:
- Cardiometabolic diseases (CVDs) are a major global health burden, driven by cardiovascular and metabolic dysregulation.
- Current treatments often involve multiple drugs, increasing complexity and risk.
Purpose of the Study:
- To review six key therapeutic targets in cardiometabolic regulation.
- To analyze structural features governing ligand efficacy and specificity.
- To guide the design of next-generation multi-target ligands for integrated therapy.
Main Methods:
- Analysis of curated structural datasets for six targets: GLP-1R, GIPR, FGFR1/β-Klotho, PCSK9, NF-κB, and NLRP3 inflammasome.
- Mapping of key binding domain features.
- Review of existing literature on dual agonists and inhibitors.
Main Results:
- Dual GLP-1R/GIPR agonists (e.g., tirzepatide) improve glycemic control and weight.
- Inhibitors of PCSK9, NF-κB, and NLRP3 reduce cholesterol and inflammation, offering cardioprotection.
- Complementary binding motifs across targets identified for rational drug design.
Conclusions:
- Next-generation multi-target ligands can offer combined cardiovascular and metabolic benefits.
- Integrated agents may reduce risks associated with complex drug combinations.
- Targeting multiple pathways simultaneously represents a promising therapeutic strategy for CVDs.
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