基因网络分析与临床前研究相结合,确定并阐明治疗帕金森病的新型不可逆 Keap1 抑制剂的作用机制。

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED Molecular Diversity Pub Date : 2024-08-15 DOI:10.1007/s11030-024-10965-y
Monisha Arumugam, Ranjith Sanjeeve Pachamuthu, Emdormi Rymbai, Aditya Prakash Jha, Kalirajan Rajagopal, Ram Kothandan, Santhoshkumar Muthu, Divakar Selvaraj
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引用次数: 0

摘要

Keap1的半胱氨酸残基(如C151、C273和C288)对其抑制Nrf2的活性至关重要。然而,迄今为止,尚未发现能共价修饰这三个半胱氨酸残基以激活 Nrf2 的分子。因此,在这项研究中,我们的目标是发现能与所有三个半胱氨酸残基发生迈克尔加成反应的新 Keap1 共价抑制剂。我们使用 Modeller v10.4 对 Keap1 的中间区域进行了建模。使用 CovDock 计算了共价对接和结合自由能。分子动力学(MD)使用 Desmond 进行。进行了各种体外试验,以确认命中分子在 6-OHDA 处理的 SH-SY5Y 细胞中的神经保护作用。此外,还在体内评估了最佳靶点是否能够改善鱼藤酮诱导的雄性大鼠姿势不稳定性和认知障碍。最后,研究人员利用网络药理学总结了最佳分子的完整分子机制。研究发现 Chalcone 和 plumbagin 能与所有三个半胱氨酸残基形成必要的共价键。但 MD 分析表明,Plumbagin 的结合比 Chalcone 更稳定。浓度为 0.01 和 0.1 μM 的 Plumbagin 对 6-OHDA 处理的 SH-SY5Y 细胞具有神经保护作用。0.1 µM浓度的Plumbagin对活性氧的形成和谷胱甘肽水平有积极影响。Plumbagin 还能改善经鱼藤酮治疗的雄性大鼠的姿势不稳定性和认知障碍。我们的网络分析表明,Plumbagin 还能改善多巴胺信号传导。此外,昆布素还能通过激活 Nrf2 发挥抗氧化和抗炎活性。综上所述,我们的研究表明,Plumbagin 是一种新型 Keap1 共价抑制剂,可用于 Nrf2 介导的帕金森病神经保护。
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Gene network analysis combined with preclinical studies to identify and elucidate the mechanism of action of novel irreversible Keap1 inhibitor for Parkinson's disease.

The cysteine residues of Keap1 such as C151, C273, and C288 are critical for its repressor activity on Nrf2. However, to date, no molecules have been identified to covalently modify all three cysteine residues for Nrf2 activation. Hence, in this study, our goal is to discover new Keap1 covalent inhibitors that can undergo a Michael addition with all three cysteine residues. The Keap1's intervening region was modeled using Modeller v10.4. Covalent docking and binding free energy were calculated using CovDock. Molecular dynamics (MD) was performed using Desmond. Various in-vitro assays were carried out to confirm the neuroprotective effects of the hit molecule in 6-OHDA-treated SH-SY5Y cells. Further, the best hit was evaluated in vivo for its ability to improve rotenone-induced postural instability and cognitive impairment in male rats. Finally, network pharmacology was used to summarize the complete molecular mechanism of the hit molecule. Chalcone and plumbagin were found to form the necessary covalent bonds with all three cysteine residues. However, MD analysis indicated that the binding of plumbagin is more stable than chalcone. Plumbagin displayed neuroprotective effects in 6-OHDA-treated SH-SY5Y cells at concentrations 0.01 and 0.1 μM. Plumbagin at 0.1 µM had positive effects on reactive oxygen species formation and glutathione levels. Plumbagin also improved postural instability and cognitive impairment in rotenone-treated male rats. Our network analysis indicated that plumbagin could also improve dopamine signaling. Additionally, plumbagin could exhibit anti-oxidant and anti-inflammatory activity through the activation of Nrf2. Cumulatively, our study suggests that plumbagin is a novel Keap1 covalent inhibitor for Nrf2-mediated neuroprotection in PD.

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来源期刊
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
期刊介绍: Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;
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