摘要
背景：胆碱酯酶抑制剂是治疗阿尔茨海默病（AD）的第一线治疗方法，然而，现在已确定它们仅提供暂时和症状缓解，此外还具有几种遗传性副作用。因此，替代药物发现方法被用于识别新的和更安全的“疾病调节药物”。 方法：在此，我们筛选了646个天然来源的小分子，通过计算机对接研究报告了药理学和功能价值，以预测具有调节乙酰胆碱代谢潜力的更安全的神经调节分子。此外，通过体外测定确定预测分子抑制乙酰胆碱酯酶（AChE）活性的潜力和保护神经元免于变性的能力。 结果：基于in-silico AChE相互作用研究，我们预测槲皮素，咖啡因，抗坏血酸和没食子酸是潜在的AChE抑制剂。我们通过体外AChE抑制试验证实了这些分子的AChE抑制潜力，并与多奈哌齐和begacestat比较了结果。草药分子显着抑制酶活性，并且对槲皮素和咖啡因的抑制与多奈哌齐没有显示出任何显着差异。此外，测试的分子对原代（E18）海马神经元没有任何神经毒性。我们观察到槲皮素和咖啡因显着改善神经元存活并有效保护海马神经元免受HgCl2诱导的神经变性，其他分子，包括多奈哌齐和begacestat，都没有做到。 结论：槲皮素和咖啡因具有作为“疾病调节药物”的潜力，可能适用于AD等神经系统疾病的治疗。
关键词: 阿尔茨海默病，分子对接，分子动力学模拟，神经毒性，蛋白质 - 配体相互作用，原代神经元培养。
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