Journal
PHARMACEUTICALS
Volume 15, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/ph15060740
Keywords
glucagon-like peptide-1; GLP-1 receptor agonist; functional protein design; molecular dynamics simulation; long-acting antihyperglycemic
Categories
Funding
- Major Projects of Science and Technology of Anhui Province [202103a06020003]
- Key Research, China National Key Research and Development Program [2019YFA0904300, 2019YFA0904304]
- Development Plan of Anhui Province [1804b06020342]
- National Natural Science Foundation of China [91953101]
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In this study, we analyzed the structures of human GLP-1, DPP-4, and GLP-1 receptors and designed new GLP-1 receptor agonists that improved stability. Molecular modeling, molecular dynamics calculations, and simulations were used to obtain possible tertiary structure models and docking results with DPP-4 and GLP-1R. The modified GLP-1RAs effectively prevented degradation by DPP-4 while maintaining their ability to bind to GLP-1R. This research provides important insights for the development of GLP-1RAs and demonstrates the application of structural biology-based protein design in drug development.
Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and GLP-1 receptor structures and designed three GLP-1RAs, which were introduced into fusion protein fragments and changed in the overall conformation. This modification effectively prevented GLP-1RAs from entering the DPP-4 active center without affecting GLP-1RAs' ability to bind to GLP-1R, the new GLP-1RA hypoglycemic effect lasting for >24 h. Through molecular modeling, molecular dynamics calculation, and simulation, possible tertiary structure models of GLP-1RAs were obtained; molecular docking with DPP-4 and GLP-1R showed access to the fusion protein. The overall conformational change of GLP-1RAs prevented DPP-4 binding, without affecting GLP-1RAs' affinity to GLP-1R. This study provides important drug design ideas for GLP-1RA development and a new example for application of structural biology-based protein design in drug development.
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