PDF(Pubmed)
Abstract：
Parkinson\'s disease (PD) is one of the large-scale health issues detrimental to human quality of life, and current treatments are only focused on neuroprotection and easing symptoms. This study evaluated in silico binding activity and estimated the stability of major metabolites in the roots of R. palmatum (RP) with main protein targets in Parkinson\'s disease and their ADMET properties. The major metabolites of RP were subjected to molecular docking and QSAR with α-synuclein, monoamine oxidase isoform B, catechol o-methyltransferase, and A2A adenosine receptor. From this, emodin had the greatest binding activity with Parkinson\'s disease targets. The chemical stability of the selected compounds was estimated using density functional theory analyses. The docked compounds showed good stability for inhibitory action compared to dopamine and levodopa. According to their structure-activity relationship, aloe-emodin, chrysophanol, emodin, and rhein exhibited good inhibitory activity to specific targets. Finally, mediocre pharmacokinetic properties were observed due to unexceptional blood-brain barrier penetration and safety profile. It was revealed that the major metabolites of RP may have good neuroprotective activity as an additional hit for PD drug development. Also, an association between redox-mediating and activities with PD-relevant protein targets was observed, potentially opening discussion on electrochemical mechanisms with biological functions.
摘要：
帕金森病(PD)是危害人类生活质量的大规模健康问题之一,目前的治疗方法仅集中在神经保护和缓解症状。这项研究评估了计算机结合活性，并评估了在帕金森病中具有主要蛋白质靶标的R.palmatum（RP）根中主要代谢物的稳定性及其ADMET特性。RP的主要代谢物与α-突触核蛋白进行分子对接和QSAR，单胺氧化酶亚型B，儿茶酚邻甲基转移酶，和A2A腺苷受体。由此,大黄素对帕金森病靶点具有最大的结合活性。使用密度泛函理论分析估计所选化合物的化学稳定性。与多巴胺和左旋多巴相比，对接的化合物显示出良好的抑制作用稳定性。根据它们的结构-活动关系，芦荟大黄素,大黄酚,大黄素,大黄酸对特定靶标表现出良好的抑制活性。最后,由于异常的血脑屏障渗透和安全性，观察到平庸的药代动力学特性。结果表明，RP的主要代谢产物可能具有良好的神经保护活性，这对PD药物的开发具有重要意义。此外，观察到氧化还原介导和活性与PD相关蛋白靶标之间的关联，关于具有生物功能的电化学机制的潜在开门见山的讨论。
