相关实验视频

Updated: Jul 14, 2025

A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors

A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors

Published on: June 8, 2022

斯芬戈-1-酸盐受体选择性的结构决定因素

Friederike Wunsch¹, Trung Ngoc Nguyen², Gerhard Wolber²

¹Faculty of Chemistry and Pharmacy, Institue for Pharmaceutical and Medical Chemistry, University of Münster, Münster, Germany.

Archiv der Pharmazie

|October 8, 2023

概括

芬戈利莫德-1-酸盐 (F1P) 向所有斯芬戈-1-酸盐受体 (S1PRs),导致副作用. 新的选择性S1PR1,5配体如siponimod通过避免S1PR3相互作用提供了改进的治疗选择.

科学领域:

药理学药理学是指药理学的学科.
计算化学的计算化学
神经科学是一个神经科学.

背景情况:

芬戈利莫德是一种基-1-酸盐受体 (S1PR) 调节剂,是治疗多发性硬化症的第一个药物,但它对S1PR亚型的非选择性作用会引起不良影响.
在S1PR1的激动作用中介于治疗性免疫调节,而S1PR3的激动作用与心脏问题有关,推动了对选择性化合物的需求.
第二代S1PR调节剂如西波尼莫德和奥萨尼莫德对S1PR1和S1PR5具有选择性,旨在减轻副作用.

研究的目的:

使用分子动力学和药模拟来阐明S1PR亚型特定的结合部位特征.
为了可视化受体-连接体相互作用的微妙差异,用于开发选择性S1PR调节器.
了解批准的药物和工具化合物的选择性概况的机制基础.

主要方法:

结合分子动力学 (MD) 模拟与三维药 (dynophores).
在S1PR亚型中分析了结合部位特征和受体-连接体相互作用.
研究了fingolimod-1-phosphate (F1P) 和sphingosine-1-phosphate的结合动力学.

主要成果:

在S1PR正囊中确定了F1P和sphingosine-1-phosphate的独特结合模式动态.
在S1PR亚型中可视化了连接体相互作用的微妙差异.
提供了对奥萨尼莫德和西波尼莫德等药物的选择性结构基础的见解.

结论:

该研究提供了一种方法来表征S1PR亚型的特定结合,有助于选择性配体的设计.
了解绑定动态对于开发更安全,更有效的S1PR调制器至关重要.
这些发现有助于对现有的S1PR药物的机制理解,并指导未来的药物发现工作.

关键词:

在GPCR中,GPCR是指GPCR.药物设计药物设计分子动力学分子动力学药物学家是药物学家.选择性的选择性

更多相关视频

Construction of Model Lipid Membranes Incorporating G-protein Coupled Receptors GPCRs

Construction of Model Lipid Membranes Incorporating G-protein Coupled Receptors GPCRs

Published on: February 5, 2022

Rapid Assessment of Membrane Protein Quality by Fluorescent Size Exclusion Chromatography

Rapid Assessment of Membrane Protein Quality by Fluorescent Size Exclusion Chromatography

Published on: January 6, 2023

相关概念视频

Dose-Response Relationship: Selectivity and Specificity

Dose-Response Relationship: Selectivity and Specificity

Drugs exert their therapeutic effects by interacting with receptors, enzymes, or ion channels that are present throughout the human body. The strength and duration of the interaction between a drug and its target receptor are characterized by the selectivity and specificity of the drug. Selectivity refers to a drug's strong preference for its intended target over other targets. For instance, isoprenaline, a non-selective β-adrenergic agonist, interacts with both β1- and...

Asymmetric Lipid Bilayer

Asymmetric Lipid Bilayer

Biological membranes show uneven distribution of different types of lipids in the inner and outer layers, resulting in transverse asymmetric membranes. The treatment of the erythrocyte membrane with the enzyme phospholipase confirmed the asymmetric nature of the lipid bilayer. The enzyme hydrolyzes lipids into fatty acids and hydrophilic groups. The phospholipase acts only on the outer layer of the membrane, while the inner layer remains intact. The phospholipase treatment resulted in 80%...

Phosphoinositides and PIPs

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...

Adrenergic Agonists: Chemistry and Structure-Activity Relationship

Adrenergic Agonists: Chemistry and Structure-Activity Relationship

Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...

IP3/DAG Signaling Pathway

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...

Regulation of Nuclear Protein Sorting

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...