ArticleScientific reports2024
Molecular dynamics-guided optimization of BGM0504 enhances dual-target agonism for combating diabetes and obesity.
Article in Scientific reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
10 citing papers in PubMed.
- Evaluation of the Safety, Efficacy and Pharmacokinetics of BGM0504 in Chinese Adults With Type 2 Diabetes: A Multicentre, Randomised, Controlled and Double-Blind Phase II Trial.Diabetes, obesity & metabolism · 2026Trial
- The evolving landscape of obesity pharmacotherapy.Nature reviews. Drug discovery · 2026Review
- The promoting roles of GLP1R and GIPR in stemness maintenance and multiple lineage-specific differentiation of PDLSCs.Cellular & molecular biology letters · 2026Article
- Activating protein kinases to treat diseases: Current understanding and future challenges.Acta pharmaceutica Sinica. B · 2026Review
- Tirzepatide in Metabolically Dysfunctional-Associated Steatohepatitis (MASH): A Bibliometric and Evidence-Based Review.Journal of diabetes research · 2026Review
- Discovering bioactive pharmaceuticals from natural products for type 2 diabetes mellitus using network pharmacology, molecular docking, and molecular dynamics.Scientific reports · 2025Article
- Effect of a Low Electrostatic Environment on the Helical Structures of Peptides and Proteins Using Flexible Water Models: An In Silico Study.ACS omega · 2025Article
- Engineered GLP-1R-targeting nanoplatforms: multimodal therapeutics in human diseases.Journal of nanobiotechnology · 2025Review
- Exploring the Protective Effects of Traditional Antidiabetic Medications and Novel Antihyperglycemic Agents in Diabetic Rodent Models.Pharmaceuticals (Basel, Switzerland) · 2025Review
- GLP-1R as a potential link between diabetes and Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
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Authors and funding
15 authors.
Funding
Abstract
The dual activation of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising therapeutic strategy for managing type 2 diabetes and obesity. Tirzepatide, a dual agonist peptide, has exhibited superior clinical efficacy in glycemic and weight control compared to selective GLP-1R agonists. Nevertheless, the structural basis of Tirzepatide's extended half-life, attributed to an acylation side chain on the parent peptide, raises questions regarding its partial agonistic activity. Employing molecular dynamics simulations, we explored the dynamic processes of peptide-receptor interactions. We uncovered a crucial salt bridge between parent peptide and GLP-1R/GIPR at K20, a feature not discernible in cryo-electron microscopy structures. Building upon these insights, we developed an optimization strategy based on the parent peptide which involved repositioning the acylation side chain. The results of both in vitro and in vivo experiments demonstrated that the optimized peptide has twofold to threefold increase in agonistic activity compared to Tirzepatide while maintaining its extended half-life in plasma. This led to the design of BGM0504, which proved to be more effective than its predecessor, Tirzepatide, in both laboratory and animal studies.
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