دورية أكاديمية
Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists
| العنوان: | Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists |
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| المؤلفون: | Lei Sun, Zhi-Ming Zheng, Chang-Sheng Shao, Zhi-Yong Zhang, Ming-Wei Li, Li Wang, Han Wang, Gen-Hai Zhao, Peng Wang |
| المصدر: | Pharmaceuticals, Vol 15, Iss 6, p 740 (2022) |
| بيانات النشر: | MDPI AG, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Medicine LCC:Pharmacy and materia medica |
| مصطلحات موضوعية: | glucagon-like peptide-1, GLP-1 receptor agonist, functional protein design, molecular dynamics simulation, long-acting antihyperglycemic, Medicine, Pharmacy and materia medica, RS1-441 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1424-8247 |
| Relation: | https://www.mdpi.com/1424-8247/15/6/740; https://doaj.org/toc/1424-8247 |
| DOI: | 10.3390/ph15060740 |
| URL الوصول: | https://doaj.org/article/5f36f69b090c413381794387ff2c286f |
| رقم الأكسشن: | edsdoj.5f36f69b090c413381794387ff2c286f |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14248247 |
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| DOI: | 10.3390/ph15060740 |