Chen Kuan-Chung, Chen Kuen-Bao, Chen Hsin-Yi, Chen Calvin Yu-Chian
School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan ; Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan ; Department of Anesthesiology, China Medical University Hospital, Taichung 40447, Taiwan.
Biomed Res Int. 2014;2014:189495. doi: 10.1155/2014/189495. Epub 2014 Jun 25.
A recent research in cancer research demonstrates that tumor-specific pyruvate kinase M2 (PKM2) plays an important role in chromosome segregation and mitosis progression of tumor cells. To improve the drug development of TCM compounds, we aim to identify potent TCM compounds as lead compounds of PKM2 regulators. PONDR-Fit protocol was utilized to predict the disordered disposition in the binding domain of PKM2 protein before virtual screening as the disordered structure in the protein may cause the side effect and downregulation of the possibility of ligand to bind with target protein. MD simulation was performed to validate the stability of interactions between PKM2 proteins and each ligand after virtual screening. The top TCM compounds, saussureamine C and precatorine, extracted from Lycium chinense Mill. and Abrus precatorius L., respectively, have higher binding affinities with target protein in docking simulation than control. They have stable H-bonds with residues A:Lys311 and some other residues in both chains of PKM2 protein. Hence, we propose the TCM compounds, saussureamine C and precatorine, as potential candidates as lead compounds for further study in drug development process with the PKM2 protein against cancer.
一项近期的癌症研究表明，肿瘤特异性丙酮酸激酶M2（PKM2）在肿瘤细胞的染色体分离和有丝分裂进程中发挥着重要作用。为了改进中药化合物的药物研发，我们旨在鉴定强效中药化合物作为PKM2调节剂的先导化合物。在虚拟筛选之前，利用PONDR-Fit程序预测PKM2蛋白结合域中的无序构象，因为蛋白质中的无序结构可能会导致副作用并降低配体与靶蛋白结合的可能性。虚拟筛选后，进行分子动力学（MD）模拟以验证PKM2蛋白与每个配体之间相互作用的稳定性。分别从枸杞和相思子中提取的顶级中药化合物，即索苏胺C和相思豆毒蛋白，在对接模拟中与靶蛋白的结合亲和力高于对照。它们与PKM2蛋白两条链中的残基A：Lys311和其他一些残基形成稳定的氢键。因此，我们提出中药化合物索苏胺C和相思豆毒蛋白作为潜在的候选先导化合物，用于在针对癌症的PKM2蛋白药物研发过程中进行进一步研究。
