探索莨菪在阿尔茨海默病治疗中的潜力：硅学方法

IF 1.5 Q2 MEDICINE, GENERAL & INTERNAL

Journal of Taibah University Medical Sciences Pub Date : 2024-09-19 DOI:10.1016/j.jtumed.2024.09.003

Riyan A.P. Irsal M.Si , Gusnia M. Gholam M.Si , Maheswari A. Dwicesaria M.Si , Tiyara F. Mansyah S.Si , Fernanda Chairunisa M.Si

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引用次数: 0

摘要

目的阿尔茨海默病（AD）对全球的威胁日益严重，目前缺乏有效的治疗方法。因此，本研究旨在探索秋黄芩（Scabiosa columbaria）中的植物化学物质对乙酰胆碱酯酶（AChE）、β位点APP裂解酶1（BACE1）和TNF-α转换酶（TACE）的抑制作用。S. columbaria 含有多种生物活性化合物，如绿原酸、芳樟醇和儿茶素，它们具有解毒特性，能够抵御和控制有害湿气的积聚，并在 COVID-19 中发挥治疗作用。一些研究还表明，S. columbaria 提取物具有很强的抗氧化活性，有可能减轻 AD 的神经炎症。因此，本研究调查了 S. columbaria 植物化学物质与与 AD 相关的关键酶之间的相互作用，从而为开发新的候选疗法提供机会。评估了ADMET概况和毒性。结果所有配体都符合 Lipinski 规则并显示出低毒性。与已知药物加兰他敏相比，儿茶素类化合物显示出更高的抑制活性，并与 AChE 上更多的活性位点相互作用，因此可能具有更高的疗效。此外，绿原酸对 TACE 的抑制活性比对照药物（芳基磺酰胺）更强，这表明其作用机制不同。MD 模拟显示，所形成的复合物具有良好的稳定性。结论由于绿原酸对 TACE 的亲和力以及氢键增强配体与受体之间的相互作用等特性，S. columbaria 衍生物化合物是很有前途的候选药物。MD 模拟显示了稳定的配体-蛋白质复合物，回转半径和 MM-PBSA 计算显示了良好的结合能和相互作用能。我们的研究结果证明了所发现的化合物具有进一步开发药物的潜力。

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Exploring the potential of Scabiosa columbaria in Alzheimer's disease treatment: An in silico approach

Objectives

Alzheimer's disease (AD) is posing an increasing global threat and currently lacks effective treatments. Therefore, this study was aimed at exploring phytochemicals in Scabiosa columbaria (S. columbaria) as inhibitors of acetylcholinesterase (AChE), β-site APP cleavage enzyme 1 (BACE1), and TNF-α converting enzyme (TACE) in AD. S. columbaria contains various bioactive compounds, such as chlorogenic acid, linalool, and catechins, which are known for their detoxification properties, capacity to resist and manage harmful moisture buildup, and therapeutic roles in COVID-19. Several studies have also shown that S. columbaria extract has strong antioxidant activity, and may potentially decrease neuroinflammation in AD. Therefore, this study investigated the interactions between S. columbaria phytochemicals and key enzymes associated with AD, thus providing opportunities for the development of new therapeutic candidates.

Methods

A total of 27 phytochemicals were evaluated for their inhibitory activity against AChE, BACE1, and TACE with YASARA Structure. ADMET profiles and toxicity were assessed. The top candidate compounds underwent 100 ns MD simulations.

Results

All ligands met Lipinski's rule and showed low toxicity. Catechins, compared with the known drug galantamine, showed higher inhibitory activity and interacted with additional active sites on AChE, thus suggesting potentially higher efficacy. Moreover, chlorogenic acid showed stronger inhibitory activity against TACE than the control drug (aryl-sulfonamide), thereby suggesting a different mechanism of action. MD simulation revealed that the formed complexes had good stability. However, further exploration is necessary.

Conclusion

S. columbaria derivative compounds are promising drug candidates because of their properties, including the affinity of chlorogenic acid toward TACE and hydrogen bond enhancing ligand–receptor interactions. MD simulation indicated stable ligand–protein complexes, and the radius of gyration and MM-PBSA calculations revealed favorable binding and interaction energies. Our findings demonstrate the identified compounds' potential for further drug development.

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