PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD) is a neurological disease, and its signs and symptoms appear slowly over time. Although current Alzheimer\'s disease treatments can alleviate symptoms, they cannot prevent the disease from progressing. To accurately diagnose and treat Alzheimer\'s disease, it is therefore necessary to establish effective methods for diagnosis. Apolipoprotein E4 (ApoE4), the most frequent genetic risk factor for AD, is expressed in more than half of patients with AD, making it an attractive target for AD therapy. We used molecular docking simulations, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations to investigate the specific interactions between ApoE4 and the naturally occurring compounds found in the plant Moringa Oleifera. According to the FMO calculations, quercetin had the highest binding affinity to ApoE4 among the sixteen compounds because its hydroxyl groups generated strong hydrogen bonds with the ApoE4 residues Trp11, Asp12, Arg15, and Asp130. As a result, we proposed various quercetin derivatives by introducing a hydroxyl group into quercetin and studied their ApoE4 binding properties. The FMO data clearly showed that adding a hydroxyl group to quercetin improved its binding capacity to ApoE4. Furthermore, ApoE4 Trp11, Asp12, Arg15, and Asp130 residues were discovered to be required for significant interactions between ApoE4 and quercetin derivatives. They had a higher ApoE4 binding affinity than our previously proposed epicatechin derivatives. Accordingly, the current results evaluated using the ab initio FMO method will be useful for designing potent ApoE4 inhibitors that can be used as a candidate agent for AD treatment.
摘要：
阿尔茨海默病(AD)是一种神经系统疾病,随着时间的推移，它的症状和体征会慢慢出现。虽然目前的阿尔茨海默病治疗可以缓解症状，他们不能阻止疾病的发展。为了准确诊断和治疗阿尔茨海默病，因此有必要建立有效的诊断方法。载脂蛋白E4（ApoE4），AD最常见的遗传危险因素，在超过一半的AD患者中表达，使其成为AD治疗的有吸引力的目标。我们用分子对接模拟,经典分子力学优化，和从头算片段分子轨道（FMO）计算，以研究ApoE4与植物辣木中天然存在的化合物之间的特定相互作用。根据FMO的计算,在16种化合物中，槲皮素对ApoE4的结合亲和力最高，因为其羟基与ApoE4残基Trp11，Asp12，Arg15和Asp130产生强氢键。因此,我们通过将羟基引入槲皮素中提出了各种槲皮素衍生物，并研究了它们的ApoE4结合性质。FMO数据清楚地表明,向槲皮素添加羟基改善了其对ApoE4的结合能力。此外，发现ApoE4Trp11，Asp12，Arg15和Asp130残基是ApoE4和槲皮素衍生物之间的显着相互作用所必需的。它们具有比我们先前提出的表儿茶素衍生物更高的ApoE4结合亲和力。因此，使用从头算FMO方法评估的当前结果将有助于设计可用作AD治疗候选药物的有效ApoE4抑制剂.
