# Protein–Ligand Interactions in Cardiometabolic Drug Targets: Focus on Weight Loss and Cardioprotection

## TL;DR

This review explores how specific proteins involved in heart and metabolic diseases interact with drugs, aiming to improve weight loss and heart protection through better drug design.

## Contribution

The paper provides structural insights into six cardiometabolic drug targets to guide the design of multi-target ligands for integrated therapeutic effects.

## Key findings

- Dual GLP-1R/GIPR agonists like tirzepatide show improved glycemic control and weight reduction.
- Inhibiting PCSK9, NF-κB, and NLRP3 reduces cholesterol and inflammation, offering cardioprotection.
- Structural analysis reveals complementary motifs that can guide the development of next-generation multi-target ligands.

## 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.