Type 2 diabetes and obesity have become a global epidemic and pose a major threat to human health. Current treatments include lifestyle modification, oral medications, insulin therapy, and surgical intervention. Yuan J et al. utilized AI-assisted methods to find crucial salt bridges that are difficult to discover with traditional methods. The dual-target agonist can be applied to treat type 2 diabetes and obesity, not only with higher activity but also with a longer half-life in plasma.
GLP-1R and GIPR are highly regarded targets for the treatment of type 2 diabetes and obesity. Tirzepatide is a dual agonist peptide that outperforms GLP-1R agonists in glycemic and weight control. Using molecular dynamics simulations, the research found that the key salt bridge formed between non-acetylated Tirzepatide and GLP-1R/GIPR at the K20 site can serve to stabilize the target's activated state conformation, a feature not observed in cryo-electron microscopy structures.
Based on these findings, the team enhanced agonist activity by repositioning the acetylated side chain. The molecular dynamics simulations used in the study were implemented using AI algorithms, which not only dynamically restore the process of molecular action, but also generate more interpretable results.
(1) Molecular dynamics calculation software was used to model the interaction of Tirzepatide with GLP-1R and GIPR. The researchers focused on the effects of salt bridge formation and acetylated side chains at the K20 site on the agonistic activity of the targets.
(2) Based on the simulation results, BGM0504 was designed, which optimizes the interaction with the receptor by changing the position of the acetylated side chain.
(3) A cAMP accumulation assay was performed on BGM0504 to assess its agonist activity towards GLP-1R and GIPR. And the binding affinity of BGM0504 to HSA was tested using the BLI technique.
(4) The in vivo efficacy of BGM0504 was evaluated in db/db mice, including glycemic control, insulin levels, body weight and food intake. The therapeutic efficacy of BGM0504 in diabetes and NASH was assessed in STZ + HFD-induced C57 BL/6 mice.
(5) Pharmacokinetic assessment of BGM0504, including plasma clearance, volume of distribution, half-life, and bioavailability after administration via intravenous and subcutaneous injections, was performed in SD rat and Rhesus monkey models.
(6) Finally, histological assessment, biochemical analysis and statistical analysis were performed.
Fig. 1. Structure Analysis and Optimization Strategy of Tirzepatide. (Yuan J.; et al. 2024)
As a promising long-acting GLP-1R/GIPR dual-target agonist, BGM0504 shows superior efficacy in the treatment of type 2 diabetes and obesity, and also exhibits the potential to improve liver function and lipid levels in a NASH model, which warrants further clinical research and development.
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Original Article:
Yuan J.; et al. (2024). Molecular dynamics-guided optimization of BGM0504 enhances dual-target agonism for combating diabetes and obesity. Scientific Reports. 2024, 14(1).
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