Kayyali Chair for Pharmaceutical Industry, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
Int J Mol Sci. 2022 Mar 24;23(7):3546. doi: 10.3390/ijms23073546.
A dysfunctional protein aggregation in the nervous system can lead to several neurodegenerative disorders that result in intracellular inclusions or extracellular aggregates. An early critical event within the pathogenesis of Alzheimer's disease is the accumulation of amyloid beta peptide within the brain. Natural compounds isolated from Psoralea Fructus (PF) have significant anti-Alzheimer effects as strong inhibitors of Aβ42 aggregation. Computer simulations provide a powerful means of linking experimental findings to nanoscale molecular events. As part of this research four prenylated compounds, the active ingredients of Psoralea Fructus (PF), were studied as Aβ42 accumulation inhibitors using molecular simulations modeling. In order to resolve the binding modes of the ligands and identify the main interactions of Aβ42 residues, we performed a 100 ns molecular dynamics simulation and binding free energy calculations starting from the model of the compounds obtained from the docking study. This study was able to pinpoint the key amino acid residues in the Aβ42 active site and provide useful information that could benefit the development of new Aβ42 accumulation inhibitors.
神经细胞中功能失调的蛋白质聚集可导致多种神经退行性疾病，导致细胞内包含物或细胞外聚集物。阿尔茨海默病发病机制中的早期关键事件是脑内β淀粉样肽的积累。从补骨脂（Psoralea Fructus，PF）中分离出的天然化合物是 Aβ42 聚集的强抑制剂，具有显著的抗阿尔茨海默病作用。计算机模拟为将实验结果与纳米级分子事件联系起来提供了一种强大的手段。作为这项研究的一部分，使用分子模拟建模研究了四种类异戊二烯化合物，即补骨脂（PF）的活性成分，作为 Aβ42 积累抑制剂。为了确定配体的结合模式并确定 Aβ42 残基的主要相互作用，我们从对接研究中获得的化合物模型开始进行了 100 ns 分子动力学模拟和结合自由能计算。这项研究能够确定 Aβ42 活性位点中的关键氨基酸残基，并提供有益的信息，有助于开发新的 Aβ42 积累抑制剂。
