PDF(Pubmed)
Abstract：
Glycogen synthase kinase 3-beta (GSK3-β) is a serine-threonine protease expressed in the brain, and its hyperactivity is considered the underlying cause of Alzheimer\'s disease. This enzyme requires an ATP molecule in its N-terminal lobe to phosphorylate its substrates, with the most important substrate being the Tau protein. This study focuses on the inhibitory mechanism of four naturally occurring compounds-apigenin, luteolin, rosmarinic acid, and salvianolic acid-from the Laminaceae family against GSK3-β. The orientation of the ligands within the ATP-binding pocket of GSK3-β and their binding energy were determined through molecular docking. Additionally, molecular dynamics simulations was conducted to study the conformational changes induced by the ligands in the protein structure. The results showed that apigenin and salvianolic acid achieved deeper parts of the cavity compared to luteolin and rosmarinic acid and formed stable complexes with the enzyme. In the rosmarinic acid complex, the enzyme exhibited the most exposed conformation. On the other hand, luteolin binding caused a small closure of the opening, suggesting a potentially ATP-competitive role. Our results suggest these compounds as lead candidates for the design of GSK3-β inhibitors.
摘要：
糖原合成酶激酶3-β（GSK3-β）是一种在大脑中表达的丝氨酸-苏氨酸蛋白酶，它的多动症被认为是阿尔茨海默病的根本原因。这种酶需要一个ATP分子在其N-末端叶磷酸化其底物，最重要的底物是Tau蛋白.本研究集中于四种天然存在的化合物-芹菜素的抑制机制，木犀草素,迷迭香酸,和丹酚酸-来自班层科的抗GSK3-β。通过分子对接确定GSK3-β的ATP结合袋中配体的方向及其结合能。此外,分子动力学模拟研究了配体在蛋白质结构中引起的构象变化。结果表明，芹菜素和丹酚酸与木犀草素和迷迭香酸相比，可以达到较深的空腔部分，并与酶形成稳定的复合物。在迷迭香酸复合物中，酶表现出最暴露的构象。另一方面,木犀草素结合引起开口的小闭合，提示潜在的ATP竞争作用。我们的结果表明这些化合物是设计GSK3-β抑制剂的主要候选化合物。
