在基化酶-5家族中,构造动态和抑制剂结合的合
Shubhandra Tripathi1, Rick H Cote2, Harish Vashisth1
1Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire, USA.
概括
了解固酶-5 (PDE5) 调节是治疗勃起功能障碍和心血管疾病的关键. 抑制剂稳定特定的PDE5结构,为新药开发提供了洞察力.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 固酶-5 (PDE5) 调节循环氨酸单酸盐 (cGMP) 水平,影响勃起功能障碍和心血管疾病.
- 在PDE5催化位点周围的动态结构图案影响其活动.
- 在PDE5调节中的符合性中间体在结构上仍未解决.
研究的目的:
- 调查在阿波和抑制剂结合状态下PDE5结构动态的构造动态.
- 阐明PDE5激活和抑制的调节机制.
- 为设计新型PDE5调节器提供见解.
主要方法:
- 基于采样的增强复制品交换溶液缩放 (REST2)
- 主要组成部分分析 (PCA)
- 时间滞后的独立组件分析 (tICA)
- 分子动力学 (MD) 模拟
- 温和的元动力学模拟.
主要成果:
- α14螺旋在向内 (不活跃) 和向外 (活跃) 构造之间交替,与H环螺旋折叠/展开相关.
- 艾洛斯特抑制剂埃沃迪胺有利于α14螺旋体的不活跃的内向状态.
- 竞争性抑制剂稳定了α14螺旋的活跃向外构造,同时阻断了活跃部位.
结论:
- 支持PDE5涉及α14螺旋形状变化的调节机制.
- 了解这些动态有助于合理设计PDE5抑制剂.
- 这项研究有助于开发下一代用于治疗应用的PDE5调节器.
更多相关视频
08:49Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
375
19:16The Importance of Correct Protein Concentration for Kinetics and Affinity Determination in Structure-function Analysis
Published on: March 17, 2010
20.7K
相关概念视频
Protein-Drug Binding: Mechanism and Kinetics
630
Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
630
Induced-fit Model
81.2K
Most chemical reactions in cells require enzymes—biological catalysts that speed up the reaction without being consumed or permanently changed. They reduce the activation energy needed to convert the reactants into products. Enzymes are proteins, that usually work by binding to a substrate—a reactant molecule that they act upon.
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is mainly determined by the shape and chemical...
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is mainly determined by the shape and chemical...
81.2K
Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K
Protein Kinases and Phosphatases
13.2K
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
13.2K
Cooperative Allosteric Transitions
2.3K
2.3K
Enzyme Inhibition
78.8K
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
78.8K
