School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan.
Evid Based Complement Alternat Med. 2014;2014:436863. doi: 10.1155/2014/436863. Epub 2014 Apr 29.
Protein phosphatase 2A (PP2A) is an important phosphatase which regulates various cellular processes, such as protein synthesis, cell growth, cellular signaling, apoptosis, metabolism, and stress responses. It is a holoenzyme composed of the structural A and catalytic C subunits and a regulatory B subunit. As an environmental toxin, okadaic acid, is a tumor promoter and binds to PP2A catalytic C subunit and the cancer-associated mutations in PP2A structural A subunit in human tumor tissue; PP2A may have tumor-suppressing function. It is a potential drug target in the treatment of cancer. In this study, we screen the TCM compounds in TCM Database@Taiwan to investigate the potent lead compounds as PP2A agent. The results of docking simulation are optimized under dynamic conditions by MD simulations after virtual screening to validate the stability of H-bonds between PP2A- α protein and each ligand. The top TCM candidates, trichosanatine and squamosamide, have potential binding affinities and interactions with key residues Arg89 and Arg214 in the docking simulation. In addition, these interactions were stable under dynamic conditions. Hence, we propose the TCM compounds, trichosanatine and squamosamide, as potential candidates as lead compounds for further study in drug development process with the PP2A- α protein.
蛋白磷酸酶 2A（PP2A）是一种重要的磷酸酶，调节多种细胞过程，如蛋白质合成、细胞生长、细胞信号转导、细胞凋亡、代谢和应激反应。它是由结构 A 和催化 C 亚基以及调节 B 亚基组成的全酶。作为一种环境毒素，冈田酸是一种肿瘤促进剂，与 PP2A 催化 C 亚基和人类肿瘤组织中 PP2A 结构 A 亚基的癌相关突变结合；PP2A 可能具有肿瘤抑制功能。它是癌症治疗的潜在药物靶点。在这项研究中，我们从 TCM 数据库@台湾筛选 TCM 化合物，以研究作为 PP2A 剂的潜在先导化合物。对接模拟的结果通过 MD 模拟在虚拟筛选后在动态条件下进行优化，以验证 PP2A-α 蛋白与每个配体之间氢键的稳定性。顶级 TCM 候选物，三尖杉酯碱和海鞘素，在对接模拟中与关键残基 Arg89 和 Arg214 具有潜在的结合亲和力和相互作用。此外，这些相互作用在动态条件下是稳定的。因此，我们提出 TCM 化合物，三尖杉酯碱和海鞘素，作为潜在的候选物，作为先导化合物，进一步研究 PP2A-α 蛋白在药物开发过程中的应用。
