In Silico Investigation of Traditional Chinese Medicine for Potential Lead Compounds as SPG7 Inhibitors against Coronary Artery Disease.
In Silico Investigation of Traditional Chinese Medicine for Potential Lead Compounds as SPG7 Inhibitors against Coronary Artery Disease.
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DOI：
10.3390/molecules21050588
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发表时间：
2016-05-05
期刊：
影响因子：
--
通讯作者：
Chen YC
中科院分区：
文献类型：
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作者：
Chen KB;Chen KC;Chang YL;Chang KL;Chang PC;Chang TT;Chen YC
冠状动脉疾病（CAD）是心脏病发作的最常见原因，也是世界上死亡的主要原因。它与线粒体功能障碍和活性氧产生水平增加有关。根据渥太华心脏基因组学研究全基因组关联研究，最近的一项研究发现，Q688 痉挛性截瘫 7 (SPG7) 变异与 CAD 相关，因为它绕过了 AFG3L2 酪氨酸磷酸化的调节，增强了 SPG7 蛋白的加工和成熟。本研究旨在鉴定从中药 (TCM) 中分离出的潜在化合物作为 paraplegin (SPG7) 抑制剂的潜在先导化合物。对于paraplegin的晶体结构，在虚拟筛选之前使用PONDR-Fit方案预测了结合位点中关键氨基酸的无序排列。中药化合物雪莲胺 C 和 3-(2-羧基苯基)-4(3H)-喹唑啉酮具有稳定氢键的潜在结合亲和力以及与 paraplegin 关键残基的疏水接触。进行分子动力学模拟以验证动态条件下每个候选者和截瘫者之间相互作用的稳定性。因此，我们建议这些化合物作为从中药中分离的化合物中作为先导药物的潜在候选者，以进一步研究paraplegin蛋白治疗冠状动脉疾病的药物开发过程。
Coronary artery disease (CAD) is the most common cause of heart attack and the leading cause of mortality in the world. It is associated with mitochondrial dysfunction and increased level of reactive oxygen species production. According to the Ottawa Heart Genomics Study genome-wide association study, a recent research identified that Q688 spastic paraplegia 7 (SPG7) variant is associated with CAD as it bypasses the regulation of tyrosine phosphorylation of AFG3L2 and enhances the processing and maturation of SPG7 protein. This study aims to identify potential compounds isolated from Traditional Chinese Medicines (TCMs) as potential lead compounds for paraplegin (SPG7) inhibitors. For the crystallographic structure of paraplegin, the disordered disposition of key amino acids in the binding site was predicted using the PONDR-Fit protocol before virtual screening. The TCM compounds saussureamine C and 3-(2-carboxyphenyl)-4(3H)-quinazolinone, have potential binding affinities with stable H-bonds and hydrophobic contacts with key residues of paraplegin. A molecular dynamics simulation was performed to validate the stability of the interactions between each candidate and paraplegin under dynamic conditions. Hence, we propose these compounds as potential candidates as lead drug from the compounds isolated from TCM for further study in drug development process with paraplegin protein for coronary artery disease.