Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea.
College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk 38430, Republic of Korea.
Life Sci. 2018 Oct 1;210:20-28. doi: 10.1016/j.lfs.2018.08.060. Epub 2018 Aug 28.
Morus, a member of the family Moraceae and commonly known as the mulberry, comprises a pharmaceutically important plant group whose major constituents are the moracins. Moracin derivatives have received great attention because they exhibit a diverse range of biological functionalities. However, no studies have considered the anti-Alzheimer's disease (AD) and anti-glycation potential of moracin derivatives.
We designed the current study to explore the anti-AD activity of moracin derivatives via in vitro inhibition of BACE1 and cholinesterase, their antioxidant activity via scavenging ONOO and ABTS radicals, and their anti-diabetic activity through inhibition of advanced glycation end-products (AGEs) formation. Moreover, to define the mechanism of action of moracin derivatives in depth, we performed in silico molecular modeling using a computer-assisted drug design and modeling program.
Among the four Morus-derived moracins tested, moracin S, which has a prenyl moiety in the 2-aryl benzofuran scaffold, possessed the highest BACE1 inhibitory activity. It also, in a dose-dependent fashion, decreased ONOO-mediated bovine serum albumin (BSA) nitration and formation of AGEs and amyloid cross-β structures in the glycated BSA system, and it showed notable radical scavenging activity. In addition, enzyme kinetic and molecular docking studies demonstrated that moracin S is a potent, competitive BACE1 inhibitor that could interact with key catalytic aspartyl residues.
The prenyl moiety in the 2-aryl benzofuran structure plays a crucial role in inhibition of BACE1. These in vitro and in silico results provide valuable information for the design of anti-AD drugs.
桑科植物桑属植物（俗称桑树）是一种具有重要药用价值的植物群，其主要成分是桑色素。桑色素衍生物因其具有多种生物功能而受到广泛关注。然而，目前还没有研究考虑桑色素衍生物的抗阿尔茨海默病（AD）和抗糖化潜力。
我们设计了本研究，通过体外抑制 BACE1 和胆碱酯酶、清除 ONOO 和 ABTS 自由基来探索桑色素衍生物的抗 AD 活性，以及通过抑制晚期糖基化终产物（AGEs）形成来探索其抗糖尿病活性。此外，为了深入了解桑色素衍生物的作用机制，我们使用计算机辅助药物设计和建模程序进行了计算机分子建模。
在测试的四种桑科植物来源的桑色素中，具有 2-芳基苯并呋喃骨架中 prenyl 部分的桑色素 S 对 BACE1 具有最高的抑制活性。它还以剂量依赖的方式降低了 ONOO 介导的牛血清白蛋白（BSA）硝化和糖化 BSA 系统中 AGEs 和淀粉样交叉-β 结构的形成，并且具有显著的自由基清除活性。此外，酶动力学和分子对接研究表明，桑色素 S 是一种有效的竞争性 BACE1 抑制剂，可与关键的催化天冬氨酸残基相互作用。
2-芳基苯并呋喃结构中的 prenyl 部分在抑制 BACE1 中起着关键作用。这些体外和计算机研究结果为设计抗 AD 药物提供了有价值的信息。
