一个独特的结合口袋由非正规的SAH模拟诱导,以开发强效和选择性的PRMT抑制剂
Youchao Deng1, Xiaosheng Song2, Iredia D Iyamu1
1Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
Acta pharmaceutica Sinica. B
|December 4, 2023
概括
研究人员开发了新的蛋白质氨酸甲基转移酶 (PRMT) 抑制剂. 一种新化合物YD1113作为选择性SAH替代物,为治疗剂开发提供了一个有前途的战略.
科学领域:
- 生物化学 生物化学
- 药用化学 医学化学
- 结构生物学 结构生物学
背景情况:
- 蛋白质氨酸甲基转移酶 (PRMT) 是细胞调节中的关键酶.
- 开发针对辅因子S-adenosylmethionine (SAM) 结合位点的选择性PRMT抑制剂仍然是一个挑战.
- 现有的泛PRMT抑制剂缺乏特异性,限制了它们的治疗潜力.
研究的目的:
- 发现和描述PRMTs的新型选择性抑制剂.
- 探索这些抑制剂选择性的结构基础.
- 为增强PRMT抑制设计双基质类似物.
主要方法:
- 一种新的S-adenosylhomocysteine (SAH) 替代物的化学合成,YD1113.
- 生物化学测试以确定各种PRMT的抑制效能和选择性.
- 进行X射线晶体学,以阐明YD1113在PRMT3/4.4中的结合模式.
- 双基质类似物的设计和合成,YD1290.
主要成果:
- 通过模仿SAH,YD1113强烈而有选择地抑制PRMT3,PRMT4和PRMT5.
- 晶体结构显示YD1113在PRMT3/4中诱导了一个独特的疏水口袋,解释了它的选择性.
- 双基质模拟物YD1290表现出I型PRMT的强大和选择性抑制 (IC50 < 5nmol/L).
结论:
- YD1113代表了一种有前途的非正规SAH替代品,用于开发选择性PRMT抑制剂.
- 从YD1113获得的结构洞察力为设计下一代PRMT向治疗提供了基础.
- 双基质模拟方法提供了一种实现高强度和选择性PRMT抑制的策略.
相关概念视频
01:49Conserved Binding Sites
4.2K
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
4.2K
01:19Allosteric Proteins-ATCase
5.8K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.8K