Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agentsJul 27, 2026

How Biased Signaling and Small Molecules Interact with the GLP-1 Receptor to Help Treat Type 2 Diabetes and Obesity, Based on Molecular Simulations

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 3, 2026

Abstract

Molecular dynamics simulations reveal distinct interaction patterns and structural features of GLP-1R complexes with various ligands.

GLP-1R is a significant target for treating type 2 diabetes and obesity.
Simulations were performed on GLP-1R complexes with semaglutide, tirzepatide, danuglipron, and CHU-128.
Factors such as temperature, ligand type, and signaling profile influenced GLP-1R interactions.
Distinct patterns and structural characteristics were observed for each ligand during the simulations.
These findings enhance understanding of GLP-1R activation mechanisms.

Simplified

Glucagon-like peptide-1 receptor (GLP-1R) is a class B1 G protein-coupled receptor expressed in multiple tissues and is a major therapeutic target for type 2 diabetes mellitus and obesity. Here, we investigate the mechanisms of GLP-1R binding and activation using molecular dynamics (MD) simulations of semaglutide, tirzepatide, danuglipron, and CHU-128bound GLP-1R-Gs complexes. We analyze these simulations as a function of temperature, ligand class (peptide vs. small molecule), and signaling profile (biased vs. non-biased) to assess how these factors affect GLP-1R interactions and conformational dynamics. Our results reveal distinct interaction patterns and structural features associated with each factor which persist over the MD trajectories. Together, these findings deepen our mechanistic understanding of GLP-1R agonism and further aid in the design of effective, orally available GLP-1R agonists with reduced side effects.

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PubMed

How Biased Signaling and Small Molecules Interact with the GLP-1 Receptor to Help Treat Type 2 Diabetes and Obesity, Based on Molecular Simulations

Abstract

Full Text

Funding

Competing interests

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