Structure-Based Insights into TGR5 Activation by Natural Compounds: Therapeutic Implications and Emerging Strategies...

Area of Science:

• Biochemistry
• Pharmacology
• Structural Biology

Background:

• TGR5 (Takeda G protein-coupled receptor 5) is a key regulator of energy expenditure, glucose homeostasis, thermogenesis, and gut hormone secretion.
• Dysregulation of these processes is implicated in obesity and metabolic disorders, making TGR5 a significant therapeutic target.

Purpose of the Study:

• To review the structural mechanisms of TGR5 activation by orthosteric and allosteric ligands.
• To examine the potential of various natural compounds as TGR5 modulators for metabolic benefits.
• To discuss emerging strategies for TGR5-targeted drug development.

Main Methods:

• Analysis of cryo-electron microscopy (cryo-EM) and docking-based models for TGR5 activation.
• Molecular docking simulations (CB-Dock2, PDB ID 7BW0) to assess ligand interactions within the TGR5 orthosteric pocket.
• Review of existing literature on natural compounds and TGR5 signaling.

Main Results:

• Structural models elucidate TGR5 activation mechanisms, including ligand binding dynamics and G protein coupling.
• Several natural compounds (e.g., oleanolic acid, curcumin, betulinic acid) demonstrate potential as TGR5 agonists through key orthosteric pocket interactions.
• Docking simulations support the mechanistic basis for these compounds' metabolic effects.

Conclusions:

• TGR5 presents a viable target for obesity and metabolic disorder therapeutics.
• Natural compounds offer a rich scaffold for developing TGR5 agonists.
• Novel strategies like gut-restricted agonism and AI-guided optimization promise safer and more specific TGR5-targeted drugs.