通过计算发现了细胞染色体bc1复合体的皮科莫拉Qo) 位抑制剂
1Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
Journal of the American Chemical Society
|June 14, 2012
概括
基于碎片的药物发现 (FBDD) 现在提供了一种高通量方法. 这种新型的药相关虚拟查 (PFVS) 方法可以在没有生物物理查的情况下识别强效的膜蛋白抑制剂.
科学领域:
- 药用化学 医学化学
- 结构生物学 结构生物学
- 计算机化药物发现技术
背景情况:
- 基于碎片的药物发现 (FBDD) 传统上依赖于低通量生物物理查.
- 细胞染色体bc1复合体是药物和杀菌剂开发的关键膜蛋白标.
- 开发用于膜蛋白的高通量选方法至关重要.
研究的目的:
- 开发一种新的药理相结合碎片虚拟选 (PFVS) 方法.
- 为了确定细胞染色体bc1复合物的新型,高亲和度抑制剂.
- 证明PFVS是传统FBDD的高吞吐量替代品.
主要方法:
- 开发和应用与药相关的碎片虚拟选 (PFVS) 方法.
- 在体外生化测试以确定抑制剂结合亲缘关系 (Ki).
- 进行X射线晶体学以阐明抑制剂的结合方式.
主要成果:
- 鉴定了第一个皮科莫拉范围的Q(o) 位点抑制剂,用于细胞染色体bc1复合体.
- 对最强效的化合物 (4f,Ki = 43.00 pM) 的结合亲和力得到了20507倍的改善.
- 确定了与bc1复合体结合的皮科莫拉抑制剂 (4e) 的晶体结构.
结论:
- 新的PFVS方法使膜蛋白抑制剂的高通量选成为可能.
- PFVS独立于生物物理查技术,克服了FBDD的一个主要限制.
- 这项研究在发现膜蛋白的超强抑制剂方面取得了重大进展.
更多相关视频
08:57Simultaneous Measurement of Superoxide/Hydrogen Peroxide and NADH Production by Flavin-containing Mitochondrial Dehydrogenases
Published on: February 24, 2018
14:34A Bilingual Computational Workflow for Identifying Potential PLK1 Inhibitors in American Sign Language and English
Published on: April 3, 2026
相关概念视频
Electron Transport Chain: Complex III and IV
During the electron transport chain, electrons from NADH and FADH2 are first transferred to complexes I and II, respectively. These two complexes then transfer the electrons to ubiquinol, which carries them further to complex III. Complex III passes the electrons across the intermembrane space to Cyt c, which carries them further to complex IV. Complex IV donates electrons to oxygen and reduces it to water. As electrons pass through complexes I, III, and IV, the energy released aids the pumping...
Electron Transport Chain: Complex I and II
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
The Electron Transport Chain
The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...
Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes
Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450 isoenzymes,...
