Lee Wen-Yuan, Chen Kuan-Chung, Chen Hsin-Yi, Chen Calvin Yu-Chian
Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan ; School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan ; Department of Neurosurgery, China Medical University Hospital, Taichung 40447, Taiwan.
School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
Biomed Res Int. 2014;2014:364625. doi: 10.1155/2014/364625. Epub 2014 Jun 5.
A recent research of cancer has indicated that the mutant of isocitrate dehydrogenase 1 and 2 (IDH1 and 2) genes will induce various cancers, including chondrosarcoma, cholangiocarcinomas, and acute myelogenous leukemia due to the effect of point mutations in the active-site arginine residues of isocitrate dehydrogenase (IDH), such as IDH1/R132, IDH2/R140, and IDH2/R172. As the inhibition for those tumor-associated mutant IDH proteins may induce differentiation of those cancer cells, these tumor-associated mutant IDH proteins can be treated as a drug target proteins for a differentiation therapy against cancers. In this study, we aim to identify the potent TCM compounds from the TCM Database@Taiwan as lead compounds of IDH2 R140Q mutant inhibitor. Comparing to the IDH2 R140Q mutant protein inhibitor, AGI-6780, the top two TCM compounds, precatorine and abrine, have higher binding affinities with target protein in docking simulation. After MD simulation, the top two TCM compounds remain as the same docking poses under dynamic conditions. In addition, precatorine is extracted from Abrus precatorius L., which represents the cytotoxic and proapoptotic effects for breast cancer and several tumor lines. Hence, we propose the TCM compounds, precatorine and abrine, as potential candidates as lead compounds for further study in drug development process with the IDH2 R140Q mutant protein against cancer.
最近一项癌症研究表明，异柠檬酸脱氢酶1和2（IDH1和2）基因的突变会诱发多种癌症，包括软骨肉瘤、胆管癌和急性髓性白血病，这是由于异柠檬酸脱氢酶（IDH）活性位点精氨酸残基发生点突变的影响，如IDH1/R132、IDH2/R140和IDH2/R172。由于对那些与肿瘤相关的突变IDH蛋白的抑制可能会诱导这些癌细胞分化，这些与肿瘤相关的突变IDH蛋白可被视为针对癌症的分化治疗的药物靶标蛋白。在本研究中，我们旨在从台湾中医药数据库中鉴定出有效的中药化合物作为IDH2 R140Q突变体抑制剂的先导化合物。与IDH2 R140Q突变体蛋白抑制剂AGI-6780相比，排名前两位的中药化合物，前胡丙素和相思豆碱，在对接模拟中与靶蛋白具有更高的结合亲和力。经过分子动力学模拟后，排名前两位的中药化合物在动态条件下保持相同的对接姿势。此外，前胡丙素是从鸡骨草中提取的，它对乳腺癌和几种肿瘤细胞系具有细胞毒性和促凋亡作用。因此，我们提出中药化合物前胡丙素和相思豆碱作为潜在的候选先导化合物，用于进一步研究针对IDH2 R140Q突变体蛋白的抗癌药物开发过程。
