In silico investigation of potential mTOR inhibitors from traditional Chinese medicine for treatment of Leigh syndrome.
In silico investigation of potential mTOR inhibitors from traditional Chinese medicine for treatment of Leigh syndrome.
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DOI：
10.1155/2014/139492
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发表时间：
2014
影响因子：
--
通讯作者：
Chen CY
中科院分区：
文献类型：
--
作者：
Chen KC;Lee WY;Chen HY;Chen CY
最近的一项研究表明，抑制哺乳动物雷帕霉素靶蛋白（mTOR）可以改善Leigh综合征患者的生存和健康。mTOR蛋白可以作为针对Leigh综合征和其他线粒体疾病的药物靶蛋白进行治疗。在这项研究中，我们的目的是从台湾的TCM数据库中识别有效的中药化合物作为mTOR抑制剂的先导化合物。采用PONDR-Fit方案预测mTOR蛋白的无序排列。在虚拟筛选之后，采用MD模拟来验证每个配体与mTOR蛋白在来自对接模拟的对接位姿中的相互作用的稳定性。在对接模拟中，排名靠前的TCM化合物苦苷M和针叶素与靶蛋白的结合亲和力高于对照。它们与Val 2240残基有氢键，与Trp 2239残基有π相互作用。在MD模拟之后，顶级TCM化合物在动态条件下保持相似的对接姿态。苦木苦苷M和针叶苷是从苦木中提取得到的两个居前的中药成分。本。和黄荆（Vitex negundo L.）因此，我们提出了中药化合物苦苷M和acerosin作为潜在的候选物，作为进一步研究药物开发过程中与mTOR蛋白对抗Leigh综合征和其他线粒体疾病的先导化合物。
A recent research demonstrates that the inhibition of mammalian target of rapamycin (mTOR) improves survival and health for patients with Leigh syndrome. mTOR proteins can be treated as drug target proteins against Leigh syndrome and other mitochondrial disorders. In this study, we aim to identify potent TCM compounds from the TCM Database@Taiwan as lead compounds of mTOR inhibitors. PONDR-Fit protocol was employed to predict the disordered disposition in mTOR protein before virtual screening. After virtual screening, the MD simulation was employed to validate the stability of interactions between each ligand and mTOR protein in the docking poses from docking simulation. The top TCM compounds, picrasidine M and acerosin, have higher binding affinities with target protein in docking simulation than control. There have H-bonds with residues Val2240 and π interactions with common residue Trp2239. After MD simulation, the top TCM compounds maintain similar docking poses under dynamic conditions. The top two TCM compounds, picrasidine M and acerosin, were extracted from Picrasma quassioides (D. Don) Benn. and Vitex negundo L. Hence, we propose the TCM compounds, picrasidine M and acerosin, as potential candidates as lead compounds for further study in drug development process with the mTOR protein against Leigh syndrome and other mitochondrial disorders.
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