电迷你碎片揭示了共价HDAC8抑制剂前所未有的结合部位
Aaron B Keeley1,2,3, Aleksandra Kopranovic4, Vincenzo Di Lorenzo1,2,3
1Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, H-1117 Budapest, Hungary.
Journal of medicinal chemistry
|December 19, 2023
概括
电友型MiniFrags可以绘制共价抑制剂结合部位的地图. 这种方法识别了人体基因素脱乙酶8 (HDAC8) 上潜在的全共性抑制剂位点,从而产生一种类似于的抑制剂.
科学领域:
- 药用化学 医学化学
- 化学生物学 化学生物学
- 药物发现 药物发现 药物发现
背景情况:
- 超低分子量联体 (MiniFrags) 是药物向开发的有价值的起点.
- 共价抑制剂具有独特的治疗潜力,但需要精确的向.
- 绘制潜在的结合点的地图对于设计有效的共价药物至关重要.
研究的目的:
- 开发和应用电友MiniFrags用于绘制共价抑制剂结合位点的地图.
- 为了确定人类素脱乙酶8 (HDAC8) 上潜在的全性共价结合位.
- 为HDAC8.8设计和优化一种类似的共价抑制剂.
主要方法:
- 使用谷氨试验对电友MiniFrag反应性的表征.
- 生物化学查和质谱测量用于对HDAC8.8的共价标签.
- 针对HDAC8囊蛋白的局部导向突变发生,以验证标签.
- 碎片合并和链接器优化用于化合物开发.
主要成果:
- 电友型MiniFrags成功地绘制了HDAC8.8.上的潜在的共价结合点.
- 鉴定出了三个不同的全共价结合点.
- 串联质谱测试证实了HDAC8囊蛋白的共价标记.
- 优化产生了一种具有合并碎片策略的类共价抑制剂.
结论:
- 电友型MiniFrags是识别共价抑制剂机会的有效工具.
- 这项研究确定了HDAC8.8上新的全共价抑制位点.
- 这项工作为开发针对HDAC8相关疾病的向共价疗法提供了基础.
相关概念视频
02:04Covalently Linked Protein Regulators
6.8K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
6.8K
02:25Spreading of Chromatin Modifications
8.3K
The histone proteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.
Writers
The writer...
Writers
The writer...
8.3K
02:32Histone Modification
13.3K
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone...
13.3K