缩放和加权的拉普拉西安矩阵作为GPCR配体的功能描述器
Guillermo Goode-Romero1, Laura Dominguez1
1Departamento de Fisicoquímica, Facultad de Química, Universidad Nacional Autónoma de México, Coyoacán, CDMX, Mexico.
Journal of computational chemistry
|January 17, 2025
概括
这项研究为G蛋白结合受体 (GPCR) 连接体引入了新的拓描述符. 这些新的方法有助于理解药物发现的复杂结构-活性关系.
科学领域:
- 计算化学和化学信息学
- 药理学和药物发现
- 分子建模和生物信息学
背景情况:
- G蛋白结合受体 (GPCR) 药理学对于研究,临床研究和治疗至关重要.
- 计算机辅助药物发现加速了候选药物的识别和重新定位.
- 对于GPCR配体来说,阐明结构-活性关系 (SAR) 是具有挑战性的,因为它们对结构修饰的敏感性.
研究的目的:
- 开发新的拓描述器来表征GPCR配体.
- 评估这些描述符在理解结构-功能关系方面的有用性.
- 为了评估描述器在各种GPCR连接体集上的表现.
主要方法:
- 使用拉普拉斯矩阵开发新的拓描述符.
- 描述符按原子质量和部分电荷进行加权和缩放.
- 在三组GPCR配体上进行测试:肌肉蛋白,β-上腺素和δ-阿片类受体配体.
主要成果:
- 新的拓描述器成功地描述了药物集的结构和物理化学特征.
- 这些描述符在阐明不同GPCR目标之间的结构功能关系方面显示出潜力.
- 这些方法为分析GPCR连接体发现中的复杂SAR提供了一种新方法.
结论:
- 提出的拓描述器为药物发现提供了一个有希望的工具,针对GPCRs.
- 这些描述符可以帮助克服理解结构多样化的连接体SAR的挑战.
- 这些发现有助于推进药理学和药物化学的计算方法.
相关概念视频
G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs Regulate Adenylyl Cylase Activity
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 cells.
Two...
Two...
G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
Transducer Mechanism: G Protein–Coupled Receptors
G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical, 7TM, or...
GPCRs are also called heptahelical, 7TM, or...


