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The rational discovery of multipurpose inhibitors of the ornithine decarboxylase
The FASEB Journal ( IF 4.8 ) Pub Date : 2020-08-07 , DOI: 10.1096/fj.202001222r
Xiaoying Chai 1, 2, 3 , Jingqiong Zhan 2, 4 , Jing Pan 1, 2 , Mengxi He 2 , Bo Li 2 , Jing Wang 1, 2 , Hongyan Ma 1, 2 , Yanlin Wang 2 , Sen Liu 1, 2, 3
Affiliation  

Metabolic reprograming is a hallmark of cancer, and the polyamine metabolic network is dysregulated in many cancers. Ornithine decarboxylase (ODC) is a rate‐limiting enzyme for polyamine synthesis in the polyamine metabolic network. In many cancer cells, ODC is over‐expressed, so this enzyme has been an attracting anti‐cancer drug target. In the catalysis axis (pathway), ODC converts ornithine to putrescine. Meanwhile, ODC’s activity is regulated by protein–protein interactions (PPIs), including the ODC‐OAZ1‐AZIN1 PPI axis and its monomer‐dimer equilibrium. Previous studies showed that when ODC’s activity is inhibited, the PPIs might counteract the inhibition efficiency. Therefore, we proposed that multipurpose inhibitors that can simultaneously inhibit ODC’s activity and perturb the PPIs would be very valuable as drug candidates and molecular tools. To discover multipurpose ODC inhibitors, we established a computational pipeline by combining positive screening and negative screening. We used this pipeline for the forward screening of multipurpose ligands that might inhibit ODC’s activity, block ODC‐OAZ1 interaction and enhance ODC non‐functional dimerization. With a combination of different experimental assays, we identified three multipurpose ODC inhibitors. At last, we showed that one of these inhibitors is a promising drug candidate. This work demonstrated that our computational pipeline is useful for discovering multipurpose ODC inhibitors, and multipurpose inhibitors would be very valuable. Similar with ODC, there are a lot of proteins in human proteome that act as both enzymes and PPI components. Therefore, this work is not only presenting new molecular tools for polyamine study, but also providing potential insights and protocols for discovering multipurpose inhibitors to target more important protein targets.

中文翻译:

鸟氨酸脱羧酶多用途抑制剂的合理发现

代谢重编程是癌症的标志,多胺代谢网络在许多癌症中失调。鸟氨酸脱羧酶 (ODC) 是多胺代谢网络中多胺合成的限速酶。在许多癌细胞中,ODC 过度表达,因此这种酶一直是吸引人的抗癌药物靶点。在催化轴(途径)中,ODC 将鸟氨酸转化为腐胺。同时,ODC的活性受蛋白质-蛋白质相互作用(PPI)的调节,包括ODC-OAZ1-AZIN1 PPI轴及其单体-二聚体平衡。先前的研究表明,当 ODC 的活性受到抑制时,PPI 可能会抵消抑制效率。所以,我们提出,可以同时抑制 ODC 活性和干扰 PPI 的多用途抑制剂作为候选药物和分子工具将非常有价值。为了发现多用途 ODC 抑制剂,我们通过结合阳性筛选和阴性筛选建立了计算管道。我们使用该管道对可能抑制 ODC 活性、阻断 ODC-OAZ1 相互作用并增强 ODC 非功能性二聚化的多用途配体进行前向筛选。通过结合不同的实验分析,我们确定了三种多用途 ODC 抑制剂。最后,我们表明这些抑制剂之一是有前途的候选药物。这项工作表明,我们的计算管道对于发现多用途 ODC 抑制剂很有用,而且多用途抑制剂将非常有价值。与ODC类似,人类蛋白质组中有很多蛋白质既充当酶又充当 PPI 成分。因此,这项工作不仅为多胺研究提供了新的分子工具,而且为发现多用途抑制剂以靶向更重要的蛋白质靶标提供了潜在的见解和方案。
更新日期:2020-08-07
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