N-(3,4-二甲氧基苯基)-6,7-二甲氧基喹唑啉-4-胺(TKM01)作为阿尔茨海默病防护剂的合理作用:硅学和体内观察。

IF 3.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mohd Kashif, Karthikeyan Chandrabose, Ashok Kumar Pandurangan
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引用次数: 0

摘要

阿尔茨海默病(AD)影响着数百万人,治疗方案有限,因此成为全球关注的健康问题。淀粉样蛋白 β(Aβ)、乙酰胆碱酯酶(AChE)过高导致的胆碱能系统紊乱、氧化应激(OS)、抗氧化剂减少以及神经炎症是影响阿尔茨海默病发展的关键因素。先前的研究表明,乙酰胆碱酯酶可与 Aβ 相互作用,增加 Aβ 的积累和神经毒性,因此针对乙酰胆碱酯酶和 Aβ 的治疗可能是一种治疗 AD 的潜在方法。众所周知,非甾体抗炎药(NSAIDs)可以抑制Aβ的积累。此前,4-苯胺基喹唑啉的衍生物 TKM01 已证明对 GSK-3β 有抑制作用,而 GSK-3β 是导致 AD 进展的调节因子。目前的研究包括非甾体抗炎药和 TKM01 与 Aβ 和 AChEs 靶点的分子对接研究。在所有测试化合物中,TKM01与Aβ的结合亲和力较高。分子动力学(MD)模拟证实了蛋白质-TKM01 复合物的稳定性。TKM01 还表现出良好的药物亲和性,与其他化合物相比,未发现肝毒性。此外,体外试验显示 TKM01(50-1200 µg/mL)对 AChEs 有抑制作用。在对斑马鱼幼虫大脑的体内研究中,我们发现 TKM01(120 和 240 µg/mL)可降低 AChEs 和脂质过氧化(LPO)的水平,并增加 AlCl3(80 µM)诱导的类 AD 模型中的抗氧化剂超氧化物歧化酶(SOD)和过氧化氢酶(CAT)。此外,研究还发现 TKM01 能降低促炎细胞因子 TNF-α、IL-1β 和 IL-6。目前的研究表明,TKM01可用于治疗AD。然而,要揭示细胞、亚细胞和分子机制以及在临床阶段可能产生的影响,还需要进行实验验证。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Plausible Action of N-(3,4-Dimethoxy-Phenyl)-6,7-Dimethoxyquinazoline-4-Amine (TKM01) as an Armor Against Alzheimer's Disease: In Silico and In Vivo Insights

Alzheimer's disease (AD) affects millions of people and has limited treatment options, thus making it a global health concern. Amyloid β (Aβ), a disrupted cholinergic system with high acetylcholinesterase (AChE), oxidative stress (OS), reduced antioxidants, and neuroinflammation are key factors influencing AD progression. Prior research has shown that AChE can interact with Aβ and increase its accumulation and neurotoxicity, so targeting AChEs and Aβ could be a potential therapeutic approach for AD treatment. It has been known that nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit Aβ accumulation. Previously, TKM01, a derivative of 4-anilinoquinazoline, has demonstrated inhibitory effects against GSK-3β—a regulator in AD progression. The current research included molecular docking studies of NSAIDs and TKM01 with Aβ and AChEs as targets. TKM01 exhibited a higher binding affinity with Aβ among all tested compounds. Molecular dynamic (MD) simulations confirmed the stability of the protein-TKM01 complexes. TKM01 also exhibited favorable drug-likeness properties, and no hepatoxicity was visualized in comparison with other compounds. Further, in vitro assay showed an inhibitory action of TKM01 (50–1200 µg/mL) on AChEs. In the in vivo studies on zebrafish larvae brains, we found that TKM01 (120 and 240 µg/mL) reduced the levels of AChEs and lipid peroxidation (LPO) and increased antioxidant superoxide dismutase (SOD) and catalase (CAT) in AlCl3(80 µM)-induced AD-like model. Additionally, TKM01 treatment was found to decrease pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. The current study demonstrates that TKM01 can be used to treat AD. Nonetheless, experimental validation is needed to reveal the cellular, sub-cellular, and molecular mechanisms and possible implications at a clinical stage.

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来源期刊
CiteScore
5.80
自引率
2.80%
发文量
277
审稿时长
6-12 weeks
期刊介绍: The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.
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