相关实验视频

Updated: Jun 23, 2025

Continuous IV Infusion is the Choice Treatment Route for Arginine-vasopressin Receptor Blocker Conivaptan in Mice to Study Stroke-evoked Brain Edema

Continuous IV Infusion is the Choice Treatment Route for Arginine-vasopressin Receptor Blocker Conivaptan in Mice to Study Stroke-evoked Brain Edema

Published on: September 1, 2016

托尔瓦普坦与血管压素V2受体结合的结构基础

Hong-Li Liu¹, Hai-Yang Zhong¹, Yi-Xiao Zhang¹

¹Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China.

Acta pharmacologica Sinica

|June 20, 2024

概括

托尔瓦普坦是一种血管压素V2受体对手,在进入结合口袋之前与细胞外环结合. 这项研究揭示了开发新的ADPKD治疗方法的关键相互作用.

科学领域:

药理学药理学是指药理学的学科.
生物化学生物化学
计算生物学计算生物学

背景情况:

血管压素V2受体 (V2R) 是自体主导多囊性病 (ADPKD) 的关键治疗标.
托尔瓦普坦是FDA批准的第一个用于治疗ADPKD的V2R抗剂.
了解tolvaptan与V2R的分子相互作用对于开发改进的疗法至关重要.

研究的目的:

通过使用先进的计算模拟,研究托尔瓦普坦与V2R的原子级结合机制.
为了确定参与托尔瓦-V2R复合体形成的关键残留物和构造变化.
提供结构洞察力,可以指导新型V2R对手的设计.

主要方法:

用高斯加速分子动力学 (GaMD) 模拟来建模tolvaptan与V2R.V2R的自发结合.
对活跃和不活跃的V2R构造进行了模拟.
用于实验验证模拟中识别的关键残留物的局部定向突变发生.

主要成果:

托尔瓦普坦与V2R的结合发生在两个不同的阶段:最初与细胞外环结合 (ECL2/3),然后进入口袋.
关键的氨基酸残留物 (R181,Y205,F287,F178) 被确定为对托尔瓦结合的关键.
实验验证证了这些已识别的残留物在结合过程中的作用.

结论:

这项研究阐明了tolvaptan与V2R在原子水平上的动态结合途径.
确定了关键的残留物和结合机制,为设计下一代V2R对手提供了有价值的结构信息.
这些发现有助于开发更有效的ADPKD治疗方法,以及潜在的其他V2R介导疾病.

关键词:

绑定路径的绑定路径高斯加速分子动力学 (GaMD) 模拟.托尔瓦普坦 (托尔瓦普坦) 是一个多元的东西.血管压素V2受体 (V2R) 的使用

更多相关视频

Receptor Autoradiography Protocol for the Localized Visualization of Angiotensin II Receptors

Receptor Autoradiography Protocol for the Localized Visualization of Angiotensin II Receptors

Published on: June 7, 2016

Engineering Antiviral Agents via Surface Plasmon Resonance

Engineering Antiviral Agents via Surface Plasmon Resonance

Published on: June 14, 2022

相关概念视频

Antihypertensive Drugs: Angiotensin II Receptor Blockers

Antihypertensive Drugs: Angiotensin II Receptor Blockers

In the renin-angiotensin-aldosterone system, a hormone called angiotensin II plays a crucial role. It binds to the AT1 receptors in vascular smooth muscles coupled with Gq proteins. The activation of these receptors activates an enzyme called phospholipase C, which releases two molecules: inositol trisphosphate and diacylglycerol. These molecules cause a chain reaction that leads to the phosphorylation of myosin light chains and promotes interaction between actin and myosin, leading to smooth...

ATP Driven Pumps III: V-type Pumps

ATP Driven Pumps III: V-type Pumps

V-type pumps are ATP-driven pumps found in the vacuolar membranes of plants, yeast, endosomal and lysosomal membranes of animal cells, plasma membranes of a few specialized eukaryotic cells, and some prokaryotes. They are also known as the V1Vo-ATPase, that couple ATP hydrolysis to transport protons against a concentration gradient.
The peripheral or cytosolic V1 domain with eight subunits is involved in ATP hydrolysis. The integral or transmembrane V0 domain containing at least five subunits...

Drug Binding to Blood Components

Drug Binding to Blood Components

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...

Ligand Binding Sites

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...

The Two-State Receptor Model

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...

Antihypertensive Drugs: Vasodilators

Antihypertensive Drugs: Vasodilators

Vasodilators, primarily affecting the smooth muscles within arterial and venous walls, are commonly used for hypertension treatment. Medications such as minoxidil and hydralazine primarily target arteries and arterioles, while sodium nitroprusside acts on arterioles and venules. Minoxidil, functioning as a prodrug, is metabolized by hepatic sulfotransferase into its active form, minoxidil sulfate, after oral administration. This metabolite binds to the sulfonylurea receptor (SUR) component of...