School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia.
School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia.
Molecules. 2020 Sep 2;25(17):3991. doi: 10.3390/molecules25173991.
Natural products remain a popular alternative treatment for many ailments in various countries. This study aimed to screen for potential mammalian target of rapamycin (mTOR) inhibitors from Malaysian natural substance, using the Natural Product Discovery database, and to determine the IC of the selected mTOR inhibitors against UMB1949 cell line. The crystallographic structure of the molecular target (mTOR) was obtained from Protein Data Bank, with Protein Data Bank (PDB) ID: 4DRI. Everolimus, an mTOR inhibitor, was used as a standard compound for the comparative analysis. Computational docking approach was performed, using AutoDock Vina (screening) and AutoDock 4.2.6 (analysis). Based on our analysis, asiaticoside and its derivative, asiatic acid, both from , revealed optimum-binding affinities with mTOR that were comparable to our standard compound. The effect of asiaticoside and asiatic acid on mTOR inhibition was validated with UMB1949 cell line, and their IC values were 300 and 60 µM, respectively, compared to everolimus (29.5 µM). Interestingly, this is the first study of asiaticoside and asiatic acid against tuberous sclerosis complex (TSC) disease model by targeting mTOR. These results, coupled with our in silico findings, should prompt further studies, to clarify the mode of action, safety, and efficacy of these compounds as mTOR inhibitors.
天然产物仍然是许多国家治疗许多疾病的流行替代疗法。本研究旨在使用天然产物发现数据库筛选来自马来西亚天然物质的潜在哺乳动物雷帕霉素靶蛋白 (mTOR) 抑制剂，并确定选定的 mTOR 抑制剂对 UMB1949 细胞系的 IC。分子靶标 (mTOR) 的晶体结构从蛋白质数据库中获得，蛋白质数据库 (PDB) ID：4DRI。依维莫司，一种 mTOR 抑制剂，用作比较分析的标准化合物。使用 AutoDock Vina（筛选）和 AutoDock 4.2.6（分析）进行计算对接方法。根据我们的分析，来自 的积雪草苷及其衍生物积雪草酸与 mTOR 具有最佳的结合亲和力，与我们的标准化合物相当。用 UMB1949 细胞系验证了积雪草苷和积雪草酸对 mTOR 抑制的影响，其 IC 值分别为 300 和 60 µM，而依维莫司为 29.5 µM。有趣的是，这是首次针对雷帕霉素靶蛋白 (mTOR) 研究积雪草苷和积雪草酸对结节性硬化症 (TSC) 疾病模型的作用。这些结果，加上我们的计算机研究结果，应该促使进一步的研究，以阐明这些化合物作为 mTOR 抑制剂的作用方式、安全性和功效。
