计算型体设计 共同准葡萄糖和类似葡萄糖的体-1受体
Shubham Vishnoi1, Shayon Bhattacharya1, Erica M Walsh2
1Department of Physics, Bernal Institute, University of Limerick, Limerick V94T9PX, Ireland.
Journal of chemical information and modeling
|July 31, 2023
概括
针对葡萄糖受体 (GCGR) 和葡萄糖类-1受体 (GLP-1R) 的新双作用对治疗2型糖尿病和肥胖症有前途. 这些凝聚剂旨在改善代谢控制,超出目前的单一向疗法.
科学领域:
- 生物化学和药理学 生物化学和药理学
- 药物发现和开发 药物发现和开发
- 代谢性疾病研究研究
背景情况:
- 为G蛋白结合受体 (GPCR) 疾病提供了传统疗法的可持续替代品.
- 目前针对GLP-1R进行胰岛素分泌的单激素可以抑制葡萄糖释放,影响肥胖.
- 针对GCGR和GLP-1R的双重向可以通过平衡葡萄糖和脂肪酸代谢来解决糖尿病和肥胖症.
研究的目的:
- 设计和建模优化序列,用于GCGR和GLP-1R的双重激进作用.
- 为了确定具有预测分子结合配置的序列,以便同时激活两个受体.
- 通过分子动力学模拟,建立双重协同激素的设计规则.
主要方法:
- 作为起点,利用了来自菌体显示图书馆查的酸序列.
- 采用分子动力学模拟来推导基于受体结合的设计规则.
- 为预测GCGR和GLP-1R的双重激动性而建模和优化序列.
主要成果:
- 确定了优化的序列,预测了GCGR和GLP-1R的双重激进作用.
- 从受体相互作用的分子动力学模拟得出的设计规则.
- 新设计的共激素与内源性联体相比,显示出更好的预测合结合亲和力.
结论:
- 针对GCGR和GLP-1R的双重协同激素是一种有前途的代谢障碍治疗策略.
- 设计的协同激素显示出优越的血糖和体重减轻控制的潜力.
- 进一步的实验测试是有必要的,以验证新型协同激素的治疗疗效.
更多相关视频
14:28Peptide-based Identification of Functional Motifs and their Binding Partners
Published on: June 30, 2013
12.5K
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
11.4K
相关概念视频
Glucagon-like Receptor Agonists
358
Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
358
GPCRs Regulate Adenylyl Cylase Activity
5.7K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.7K
Transducer Mechanism: Enzyme-Linked Receptors
2.5K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.5K
Dipeptidyl Peptidase 4 Inhibitors
212
Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
212
Oral Hypoglycemic Agents: Glinides
186
Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively...
186
Hypoglycemia and Glucagon
301
Without prolonged fasting, healthy individuals maintain blood glucose levels above 3.5 mM due to a well-adapted neuroendocrine counterregulatory system that effectively prevents acute hypoglycemia, a potentially life-threatening condition. The primary clinical scenarios for hypoglycemia encompass diabetes treatment, inappropriate production of endogenous insulin or insulin-like substances by tumors, and the use of glucose-lowering agents in non-diabetic individuals. Notably, hypoglycemia in the...
301
