Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, via Marengo 2, 09123, Cagliari, Italy.
Modeling and Simulations group, Biosciences Sector, Center for advanced study research and development in Sardinia (CRS4), Loc. Piscina Manna, 09010, Pula, Italy.
Sci Rep. 2018 Mar 13;8(1):4424. doi: 10.1038/s41598-018-22747-2.
Alzheimer's disease (AD) is a neurodegenerative disorder representing the leading cause of dementia and is affecting nearly 44 million people worldwide. AD is characterized by a progressive decline in acetylcholine levels in the cholinergic systems, which results in severe memory loss and cognitive impairments. Expression levels and activity of butyrylcholinesterase (BChE) enzyme has been noted to increase significantly in the late stages of AD, thus making it a viable drug target. A series of hydroxylated 2-phenylbenzofurans compounds were designed, synthesized and their inhibitory activities toward acetylcholinesterase (AChE) and BChE enzymes were evaluated. Two compounds (15 and 17) displayed higher inhibitory activity towards BChE with IC values of 6.23 μM and 3.57 μM, and a good antioxidant activity with EC values 14.9 μM and 16.7 μM, respectively. The same compounds further exhibited selective inhibitory activity against BChE over AChE. Computational studies were used to compare protein-binding pockets and evaluate the interaction fingerprints of the compound. Molecular simulations showed a conserved protein residue interaction network between the compounds, resulting in similar interaction energy values. Thus, combination of biochemical and computational approaches could represent rational guidelines for further structural modification of these hydroxy-benzofuran derivatives as future drugs for treatment of AD.
阿尔茨海默病(AD)是一种神经退行性疾病,是痴呆症的主要病因,全球有近 4400 万人受其影响。AD 的特征是胆碱能系统中的乙酰胆碱水平逐渐下降,导致严重的记忆丧失和认知障碍。研究表明,丁酰胆碱酯酶(BChE)的表达水平和活性在 AD 的晚期显著增加,因此成为一个可行的药物靶点。本研究设计、合成了一系列羟基化 2-苯基苯并呋喃类化合物,并评价了它们对乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)的抑制活性。其中两个化合物(15 和 17)对 BChE 的抑制活性较高,IC 值分别为 6.23 μM 和 3.57 μM,抗氧化活性也较好,EC 值分别为 14.9 μM 和 16.7 μM。这两种化合物对 BChE 的抑制活性具有选择性,优于 AChE。通过计算研究比较了蛋白结合口袋,并评估了化合物的相互作用指纹。分子模拟显示,化合物之间存在保守的蛋白质残基相互作用网络,导致相似的相互作用能量值。因此,生化和计算方法的结合可以为这些羟基苯并呋喃衍生物的进一步结构修饰提供合理的指导,作为治疗 AD 的潜在药物。