{"title":"鉴定潜在的植物化学物质及其对 PERK 受体介导的 UPR 通路的抑制作用,以调控神经元疾病:硅学洞察。","authors":"Shabnam Ameenudeen, Mohammad Waseem, Hemalatha S","doi":"10.1080/07391102.2023.2242495","DOIUrl":null,"url":null,"abstract":"<p><p>The endoplasmic reticulum (ER) has been considered as the key site of protein biosynthesis and maturation in the eukaryotic cell. In recent years, the sequence at the N-terminal region of translated protein has shown a particular emphasis as a signal responsible for site-specific translocation mediated by post-translational modification. Once the native conformation is not achieved, the degradation pathway is activated, and therefore the restoration of the homeostasis of ER function in UPR pathway is initiated. One of the transmembrane proteins, PKR-like ER kinase (PERK) plays a key role in the activation of UPR through the inhibition of the translation process, thus preventing the cells from apoptosis due to chronic ER stress. Dysregulation of the neuronal proteostasis often results in neuronal dysfunction and its crucially associated neurodegenerative diseases or its manifestation of neuropathic pain. The correlation between ER stress and its associated signaling cascade, namely UPR, is well established in context of neuropathological modifications. This furthermore suggests that the proteins of the signaling cascade such as PERK can serve as a potential target during the onset of neuronal damage. The aim of this study was to identify the potential phytocompounds by evaluating the physicochemical properties, Lipinski screening, ADMET and toxicity properties of the selected phytocompounds by using SwissADME, MolInspiration and pKCSM webservers, which could establish a comparatively better affinity and binding energy than the control drug as GSK2606414 in set up the treatment of the neuronal diseases through molecular docking <i>via</i> PyRx and validating their structural stability through simulation using the Sybyl software for over100ns.Communicated by Ramaswamy H. 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引用次数: 0
摘要
内质网(ER)一直被认为是真核细胞中蛋白质生物合成和成熟的关键场所。近年来,翻译蛋白质 N 端区域的序列作为翻译后修饰介导的特定位点转运信号受到特别重视。一旦达不到原生构象,降解途径就会被激活,从而启动 UPR 途径恢复 ER 功能的平衡。跨膜蛋白之一的 PKR 样 ER 激酶(PERK)通过抑制翻译过程在 UPR 激活过程中发挥关键作用,从而防止细胞因慢性 ER 应激而凋亡。神经元蛋白稳态失调通常会导致神经元功能障碍及其相关的神经退行性疾病或神经病理性疼痛。ER应激与其相关信号级联(即UPR)之间的相关性已在神经病理学改变的背景下得到证实。这进一步表明,信号级联蛋白(如 PERK)可作为神经元损伤开始时的潜在靶标。本研究的目的是通过使用 SwissADME、MolInspiration 和 pKCSM 网络服务器评估所选植物化合物的理化性质、Lipinski 筛选、ADMET 和毒性性质,从而确定潜在的植物化合物,通过 PyRx 进行分子对接,并使用 Sybyl 软件进行超过 100ns 的模拟,验证其结构稳定性,从而在治疗神经元疾病方面建立比对照药物 GSK2606414 更好的亲和力和结合能。通讯作者:Ramaswamy H. Sarma。
Identification of potential phytochemicals and their inhibitory effect on the PERK receptor mediated UPR pathway for neuronal disease regulation: an in silico insight.
The endoplasmic reticulum (ER) has been considered as the key site of protein biosynthesis and maturation in the eukaryotic cell. In recent years, the sequence at the N-terminal region of translated protein has shown a particular emphasis as a signal responsible for site-specific translocation mediated by post-translational modification. Once the native conformation is not achieved, the degradation pathway is activated, and therefore the restoration of the homeostasis of ER function in UPR pathway is initiated. One of the transmembrane proteins, PKR-like ER kinase (PERK) plays a key role in the activation of UPR through the inhibition of the translation process, thus preventing the cells from apoptosis due to chronic ER stress. Dysregulation of the neuronal proteostasis often results in neuronal dysfunction and its crucially associated neurodegenerative diseases or its manifestation of neuropathic pain. The correlation between ER stress and its associated signaling cascade, namely UPR, is well established in context of neuropathological modifications. This furthermore suggests that the proteins of the signaling cascade such as PERK can serve as a potential target during the onset of neuronal damage. The aim of this study was to identify the potential phytocompounds by evaluating the physicochemical properties, Lipinski screening, ADMET and toxicity properties of the selected phytocompounds by using SwissADME, MolInspiration and pKCSM webservers, which could establish a comparatively better affinity and binding energy than the control drug as GSK2606414 in set up the treatment of the neuronal diseases through molecular docking via PyRx and validating their structural stability through simulation using the Sybyl software for over100ns.Communicated by Ramaswamy H. Sarma.
期刊介绍:
The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.