Beigh Saba, Alsahag Mansoor, Alisaac Ali, Dar Sajad Ahmad, Alyami Mohammad H, Ajlan Soma E, Malak Hesham A, Alshehri Abdullateef Abdullah
Department of Public Health, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha, Saudi Arabia.
Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha, Saudi Arabia.
Curr Pharm Des. 2025 Jul 31. doi: 10.2174/0113816128386836250723134001.
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.
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.
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.
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.
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.
被称为阿尔茨海默病（AD）的进行性神经退行性疾病以神经炎症、β-淀粉样蛋白堆积和认知障碍为特征。尽管进行了广泛研究，但目前的药物治疗仅能缓解症状，这突出了对创新的多靶点药物的需求。由于载脂蛋白E4（ApoE4）是与AD发展相关的一个重要遗传风险因素，它是一个潜在有效的治疗靶点。像银杏内酯这样的天然物质具有神经保护特性，可能有助于治疗某些疾病。本研究调查了银杏内酯作为AD多靶点治疗药物的潜力，特别关注其与ApoE4 N端结构域的相互作用方式。
使用药代动力学分析、分子对接和分子动力学（MD）模拟评估银杏内酯与ApoE4（PDB ID：8AX8）之间的相互作用。MD模拟用于确定稳定性，AutoDock Vina用于获得结合亲和力。使用SwissADME和PkCSM预测药代动力学和毒性。通过与姜黄素和白藜芦醇的比较对接来阐明银杏内酯的有效性。
银杏内酯与重要位点形成了持续的疏水接触，并对ApoE4表现出显著的结合亲和力（-7.1千卡/摩尔）。MD模拟证实了在100纳秒内波动可忽略不计且复合物稳定性良好。药代动力学表明无明显毒性风险、良好的胃肠道吸收和有利的血脑屏障通透性。在结合亲和力和稳定性方面，银杏内酯比姜黄素和白藜芦醇表现更好，表明其具有更大的治疗潜力。
结果表明银杏内酯能有效结合并稳定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具有更广泛的治疗相关性。这些计算机模拟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。
结果表明银杏内酯通过调节ApoE4对AD可能是一种潜在有效的多靶点治疗药物。由于其强大的结合亲和力、稳定性和药代动力学，它比其他天然化合物是更好的选择。这些发现突出了计算机模拟方法在药物发现早期阶段的价值以及在可用于临床之前需要额外实验支持的必要性。
