一个虚拟的屏幕,多种类型的配体:选择性G蛋白结合受体对手的发现
Stanislav Engel1, Amanda P Skoumbourdis, John Childress
1The Clinical Endocrinology Branch and Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Journal of the American Chemical Society
|March 25, 2008
概括
一种新的虚拟查方法克服了G蛋白结合受体 (GPCR) 药物发现方面的挑战. 这种方法确定了激素释放激素受体 (TRH-R1和TRH-R2) 的新型抗体.
科学领域:
- 生物化学 生物化学
- 药理学 药理学 是一个学科.
- 计算化学的计算化学
背景情况:
- 虚拟查是识别生物活性小分子的关键,但它对G蛋白结合受体 (GPCR) 的成功是有限的.
- 由于结构数据稀缺和固有的灵活性,GPCRs存在挑战,使基于受体的虚拟查复杂化.
- 现有的方法很难解释GPCR中的结构不确定性和灵活性.
研究的目的:
- 开发和验证用于针对 GPCR 的虚拟查的 in silico 方法,以解决结构性不确定性.
- 为了确定新型的小分子对铁热素释放激素受体 (TRH-R1和TRH-R2) 的抗体.
主要方法:
- 开发了一种新的in silico方法来缓解GPCRs虚拟查中的结构不确定性.
- 使用开发的方法,从虚拟数据库中选了100万种化合物.
- 选择了100种不同的化合物进行实验验证,包括对TRH受体的突变分析.
主要成果:
- 确定了五种结构上不同的甲状腺激素释放激素受体对手 (TRH-R1和TRH-R2).
- 性对结合亲和力至关重要,其中一个立体同位素对TRH-R1比TRH-R2具有13倍的选择性.
- 突变分析证实了已识别的小分子抗剂的结合方式.
结论:
- 这种新的虚拟查方法有效地识别了GPCR对抗剂,尽管存在结构性挑战.
- 这种方法对发现其他GPCR标的新型激动剂和抗剂具有前景.
- 这些发现强调了性在TRH受体对抗剂设计中的重要性.
相关概念视频
01:15G 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...
01:15G 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...
01:21G-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.
01:21G-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.
02:40Ligand 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...
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...
02:40Ligand 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...
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...