Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, India.
Department of Biochemistry, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, India.
Int J Biol Macromol. 2020 Dec 15;165(Pt A):1323-1330. doi: 10.1016/j.ijbiomac.2020.09.232. Epub 2020 Oct 1.
Alzheimer's disease (AD) is marked by the presence of amyloid plaques, neurofibrillary tangles, oxidatively damaged neuronal macromolecules and redox sensitive ions. Reduction of amyloid plaques and oxidative stress emerge as a convincing treatment strategy. Plaque reduction is achieved by inhibition of BACE1, the rate limiting enzyme generating the prime constituent of plaques, Aβ, through proteolysis of the amyloid precursor protein. Here, we report a QSAR model with five descriptors, developed to screen natural compounds as potent BACE1 inhibitors. Seven compounds out of which five flavonols namely isorhamnetin, syringetin, galangin, tamarixetin, rhamnetin and two flavanonols namely dihydromyricetin, taxifolin were screened. The ability of these compounds were validated using the BACE1 activity assay. The antioxidant property were estimated by the DPPH and ABTS assay. Although inhibition assay implied syringetin to be a promising BACE1 inhibitor, its poor antioxidant activity leaves it less effective as a multitarget ligand. Exhibiting moderate dual ability, isorhamnetin and taxifolin qualified as multi-target scaffolds for AD therapeutics. Our study reveals the importance of 4'-OH in the B ring of flavonols and the lack of any effect of 5'-OH in flavanonols for BACE1 inhibition. In case of antioxidant activity favourable association of 3'-O-methylation derivatives was observed in flavonols.
阿尔茨海默病（AD）的特征是存在淀粉样斑块、神经原纤维缠结、氧化损伤的神经元大分子和氧化还原敏感离子。减少淀粉样斑块和氧化应激成为一种有说服力的治疗策略。通过抑制 BACE1 来减少斑块，BACE1 是产生斑块主要成分 Aβ的限速酶，通过淀粉样前体蛋白的蛋白水解来实现。在这里，我们报告了一个具有五个描述符的 QSAR 模型，该模型用于筛选潜在的 BACE1 抑制剂。在七种化合物中，有五种黄酮醇，即异鼠李素、圣草酚、柽柳素、杨梅素、山奈酚和两种黄烷酮醇，即二氢杨梅素、杨梅素被筛选出来。使用 BACE1 活性测定法对这些化合物的能力进行了验证。抗氧化性能通过 DPPH 和 ABTS 测定法进行评估。虽然抑制试验表明圣草酚是一种很有前途的 BACE1 抑制剂，但它的抗氧化活性差，使其作为多靶点配体的效果较差。异鼠李素和杨梅素表现出中等的双重能力，是 AD 治疗的多靶标支架。我们的研究揭示了黄酮醇 B 环上 4'-OH 的重要性，以及在 BACE1 抑制方面，黄烷酮醇 5'-OH 没有任何作用。在抗氧化活性方面，观察到黄酮醇 3'-O-甲基化衍生物的有利相关性。
