从基于机器学习的虚拟选中发现PRMT5 N-终端TIM桶联体
Zhihang Shen1, Gustavo Seabra1, Jason Brant2,3
1Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
ACS omega
|January 20, 2025
概括
研究人员开发了一种机器学习方法,以找到针对PRMT5/pICLn蛋白相互作用的药物. 一种化合物Z319334062抑制了质母细胞瘤细胞中的PRMT5活性,显示出癌症治疗的前景.
科学领域:
- 在瘤学瘤学.
- 生物化学 生物化学
- 计算生物学 计算生物学
背景情况:
- 蛋白质氨酸甲基转移酶5 (PRMT5) 是癌症治疗的关键标,因为它在对称蛋白质二甲基化中的作用.
- 目前的PRMT5抑制剂主要向催化域,但抑制PRMT5/pICLn蛋白质-蛋白质接口也至关重要.
- 开发小分子来破坏蛋白质与蛋白质相互作用,为治疗提供了重大机会.
研究的目的:
- 开发和应用基于机器学习的虚拟选方法,以识别PRMT5/pICLn蛋白质与蛋白质相互作用的抑制剂.
- 选可以破坏PRMT5/pICLn复合物的新型小分子.
主要方法:
- 一个基于机器学习的虚拟选管道被设计和使用.
- 从虚拟屏幕中选择了18种化合物进行实验验证.
- 使用表面等离子体共振 (SPR) 来评估结合亲和力.
主要成果:
- 一种化合物Z319334062对PRMT5/pICLn标具有结合亲和力,其KD值为21.5μM.
- Z319334062表现出对称二甲基化水平的剂量依赖抑制.
- 该化合物的有效性在患者衍生的质母细胞瘤细胞系中观察到.
结论:
- 开发的机器学习管道对于识别PRMT5/pICLn相互作用的抑制剂是有效的.
- 化合物Z319334062代表了开发新型PRMT5向癌症疗法的有前途的领导者.
- 破坏PRMT5/pICLn接口是癌症治疗的可行策略.
相关概念视频
Translocation of Proteins into the Mitochondria
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Protein Transport into the Inner Mitochondrial Membrane
Nuclear encoded mitochondrial precursors are imported to the inner membrane in a multistep process involving two separate translocons, TIM22 and TIM23. TIM23 is a cation-selective pore that remains closed by the N terminal segment of the protein. Negative charges on the TIM23 act as a receptor for the incoming precursor, pulling the positively charged matrix-targeting sequence for peptide insertion and translocation.
Transport of mitochondrial precursors across the TIM23 channel is driven by...
Transport of mitochondrial precursors across the TIM23 channel is driven by...
Real Time RT-PCR
Real-time reverse transcription-polymerase chain reaction, or Real-time RT-PCR, is an analytical tool used to determine the expression level of target genes. The method involves converting mRNA to complementary DNA with the help of an enzyme known as reverse transcriptase, followed by the PCR amplification of the cDNA. These two processes can be performed simultaneously in a single tube or separately as a two-step reaction.
The real-time quantification of the number of amplified products is...
The real-time quantification of the number of amplified products is...


