Department of Chemistry, Truman State University, Kirksville, MO 63501, USA.
Department of Pharmacology, A.T. Still University, Kirksville, MO 63501, USA.
Int J Mol Sci. 2021 Mar 12;22(6):2888. doi: 10.3390/ijms22062888.
Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer's disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aβ fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aβ disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aβ fibril via the π-π interactions. Moreover, docking scores correlate well with the ThT EC values. Molecular dynamic simulations revealed that biflavonoids decrease the content of β-sheet in Aβ fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aβ fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aβ fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer's disease.
淀粉样 β （Aβ）纤维在大脑中的沉积是阿尔茨海默病的关键病理标志。多酚类双黄酮类化合物具有抗淀粉样形成作用，可抑制 Aβ聚集并促进 Aβ纤维的解聚。在本研究中，我们进一步研究了双黄酮类化合物解聚 Aβ的结构基础及其在原子水平上的相互作用。硫黄素 T（ThT）荧光测定法表明，由于特定的结构差异，扁柏黄酮型双黄酮类化合物以不同的效力促进 Aβ纤维的解聚。本文的计算分析提供了双黄酮类化合物解聚 Aβ的机制的第一个原子细节。分子对接分析表明，双黄酮类化合物通过π-π相互作用优先与 Aβ纤维富含芳香族的部分有序 N 末端结合。此外，对接评分与 ThT EC 值很好地相关。分子动力学模拟表明，双黄酮类化合物以结构依赖性的方式降低 Aβ纤维中的β-折叠含量。氢键分析进一步支持双黄酮骨架上两个位置的羟基能够形成氢键的取代会导致 Aβ纤维的显著解聚。综上所述，我们的数据表明，双黄酮类化合物通过破坏纤维结构促进 Aβ纤维的解聚，这表明双黄酮类化合物是开发治疗阿尔茨海默病药物的一类先导化合物。
