银杏内酯作为阿尔茨海默病的有前途的多靶点治疗:靶向ApoE4和超越。

IF 2.8 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Saba Beigh, Mansoor Alsahag, Ali Alisaac, Sajad Ahmad Dar, Mohammad H Alyami, Soma E Ajlan, Hesham A Malak, Abdullateef Abdullah Alshehri
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引用次数: 0

摘要

进行性神经退行性疾病阿尔茨海默病(AD)的典型特征是神经炎症、淀粉样蛋白积累和认知障碍。尽管进行了广泛的研究,但目前的药物治疗仅能缓解症状,这强调了开发创新的多靶点药物的必要性。由于载脂蛋白E4 (ApoE4)是与AD发展相关的重要遗传风险因素,因此它是一种潜在的有效治疗靶点。像银杏内酯这样的天然物质具有神经保护作用,可能有助于治疗某些疾病。本研究探讨了银杏内酯作为AD多靶点治疗的潜力,特别强调了它如何与ApoE4 n端结构域相互作用。方法:采用药动学分析、分子对接和分子动力学模拟等方法评价银杏内酯与ApoE4 (PDB ID: 8AX8)的相互作用。MD模拟测定稳定性,AutoDock Vina测定结合亲和力。为了预测药代动力学和毒性,采用了SwissADME和PkCSM。银杏内酯的有效性与姜黄素和白藜芦醇进行了对比对接。结果:银杏内酯与ApoE4的重要位点形成持续的疏水接触,与ApoE4的结合亲和力为-7.1 kcal/mol。MD模拟验证了可忽略不计的波动和超过100 ns的复杂稳定性。药代动力学显示无明显毒性风险,胃肠道吸收良好,血脑屏障通透性良好。在结合亲和力和稳定性方面,银杏内酯表现优于姜黄素和白藜芦醇,表明银杏内酯具有更大的治疗潜力。讨论:结果表明银杏内酯有效结合并稳定ApoE4 n端结构域,支持其在调节阿尔茨海默病关键病理因素中的潜在作用。与姜黄素和白藜芦醇相比,其优越的药代动力学特征和相互作用动力学表明其具有更广泛的治疗意义。这些在计算机上的见解为进一步研究银杏内酯的神经保护作用提供了机制基础。结论:银杏内酯可通过调控ApoE4多靶点治疗AD。由于其强大的结合亲和力、稳定性和药代动力学,它是比其他天然化学物质更好的选择。这些发现强调了计算机方法在药物发现的早期阶段的价值,以及在临床应用之前需要额外的实验支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ginkgolide as a Promising Multi-Target Therapeutic for Alzheimer's Disease: Targeting ApoE4 and Beyond.

Introduction: The progressive neurodegenerative disease known as Alzheimer's disease (AD) is typified by neuroinflammation, amyloid-beta buildup, and cognitive impairment. Current pharmacological treatments merely alleviate symptoms, despite extensive research, which underscores the need for innovative, multi-target medicines. Since apolipoprotein E4 (ApoE4) is a significant genetic risk factor linked to the development of AD, it is a potentially effective treatment target. With their neuroprotective qualities, natural substances like ginkgolide may help treat some diseases. This study investigates ginkgolide's potential as a multi-target treatment for AD, with a particular emphasis on how it interacts with the ApoE4 N-terminal domain.

Methods: The interaction between Ginkgolide and ApoE4 (PDB ID: 8AX8) was assessed using pharmacokinetic profiling, molecular docking, and molecular dynamics (MD) simulations. MD simulations were used to determine stability, and AutoDock Vina was used to obtain the binding affinity. To predict pharmacokinetics and toxicity, SwissADME and PkCSM were employed. The effectiveness of ginkgolide was contextualized using comparative docking with curcumin and resveratrol.

Results: Ginkgolide formed sustained hydrophobic contacts with important sites and demonstrated a substantial binding affinity (-7.1 kcal/mol) to ApoE4. MD simulations verified negligible fluctuations and complex stability over 100 ns. Pharmacokinetics showed no significant toxicity risks, good gastrointestinal absorption, and favorable blood-brain barrier permeability. In terms of binding affinity and stability, ginkgolide fared better than curcumin and resveratrol, indicating its greater therapeutic potential.

Discussion: The results indicate that ginkgolide effectively binds and stabilizes the ApoE4 N-terminal domain, supporting its potential role in modulating a key pathological factor in Alzheimer's disease. Its superior pharmacokinetic profile and interaction dynamics compared to curcumin and resveratrol suggest a broader therapeutic relevance. These in silico insights provide a mechanistic basis for further investigation into ginkgolide's neuroprotective effects.

Conclusion: The results demonstrated ginkgolide as a potentially effective multi-target treatment for AD through ApoE4 regulation. It is a better option than other natural chemicals because of its potent binding affinity, stability, and pharmacokinetics. These findings highlight the value of in silico methods in the early stages of drug discovery and the need for additional experimental support before they can be used in clinical settings.

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来源期刊
CiteScore
6.30
自引率
0.00%
发文量
302
审稿时长
2 months
期刊介绍: Current Pharmaceutical Design publishes timely in-depth reviews and research articles from leading pharmaceutical researchers in the field, covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area guest edited by an acknowledged authority in the field. Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design including: medicinal chemistry, pharmacology, drug targets and disease mechanism.
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