图书馆查发现商业药物是异常阿波利波蛋白AI的潜在结构校正剂
Christina Gkolfinopoulou1, Angeliki Bourtsala1, Daphne Georgiadou1
1Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Athens, Greece.
Journal of lipid research
|April 19, 2024
概括
研究人员对药物进行了选,以寻找稳定具有与心血管风险相关突变的阿波利波蛋白AI (apoA-I) 的化合物. 两种药物,阿托瓦斯塔丁和贝克萨罗,恢复了正常的apoA-I结构和功能,提供了潜在的新疗法.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 心血管科学 心血管科学
背景情况:
- 高密度脂蛋白 (HDL) 对于预防动脉样硬化至关重要.
- 脂蛋白A-I (apoA-I) 是HDL中的主要蛋白质,对其结构和功能至关重要.
- 一种特定的apoA-I突变 (L178P) 导致结构缺陷,可能增加心血管风险.
研究的目的:
- 确定能够稳定突变的apoA-I (apoA-I[L178P]) 的构造的小分子.
- 评估已识别的化合物在恢复apoA-I功能和减轻心血管风险方面的潜力.
主要方法:
- 使用热转移试验和SYPRO色剂选956种已上市的药物.
- 使用8-anilinonaphthalene-1-sulfonic acid监测疏水性位点结合的对角测定.
- 循环二重化谱法用于评估二次结构和热力学稳定性.
- 巨细胞活力测定和胆固醇外流测量.
- 计算对接用于预测药物向相互作用.
主要成果:
- 从药物选中确定了四种潜在的结构校正化合物.
- 亚托瓦斯塔丁和贝克萨罗因其度依赖作用而被选择进行进一步分析.
- 这两种药物都稳定了apoA-I[L178P]结构,并恢复了巨细胞中的胆固醇去除能力.
- 计算对接表明,阿托瓦斯塔丁和贝克沙罗与apoA-I中的特定腔结合,稳定其结构.
结论:
- 小分子可以纠正apoA-I.I.中的结构和功能缺陷.
- 阿托瓦斯塔丁和贝克萨罗在apoA-I相关的脂质失调症中显示出治疗干预的前景.
- 这些发现为针对与apoA-I功能障碍相关的心血管风险的新疗法开辟了道路.
更多相关视频
相关概念视频
Structure-Activity Relationships and Drug Design
710
Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
710
Drug Discovery: Overview
7.8K
Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
7.8K
Drug Binding to Blood Components
147
When drugs enter systemic circulation, they interact with various components of the blood, including proteins such as human serum albumin (HSA), α1-acid glycoprotein (AAG), lipoproteins, globulins, and red blood cells (RBCs).
HSA is the most abundant plasma protein and is vital in drug binding. It contains distinct drug-binding sites, with different drugs exhibiting affinity for specific sites. There are three main drug-binding domains for HSA: sites I, II, and III. These domains are...
HSA is the most abundant plasma protein and is vital in drug binding. It contains distinct drug-binding sites, with different drugs exhibiting affinity for specific sites. There are three main drug-binding domains for HSA: sites I, II, and III. These domains are...
147
Targets for Drug Action: Overview
6.2K
Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
6.2K
Drug Distribution: Plasma Protein Binding
5.5K
Drugs predominantly attach to plasma proteins, with only a small percentage remaining unbound. The unbound portion can be calculated as one minus the bound fraction. Acidic drugs form large, inactive complexes by reversibly binding to plasma albumin, which prevents them from diffusing across biological barriers. These drug-protein complexes act as reservoirs for the drugs. As the concentration of unbound drugs decreases, these complexes quickly dissociate to release the free drug, maintaining...
5.5K


