Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand; Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok, 10900, Thailand.
Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand; Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok, 10900, Thailand.
Chem Biol Interact. 2021 Aug 1;344:109523. doi: 10.1016/j.cbi.2021.109523. Epub 2021 May 23.
Acetylcholinesterase (AChE) plays a vital role in Alzheimer's disease (AD), which is one of the most common causes of dementia. Discovering new effective inhibitors against AChE activity is seen to be one of the effective approaches to reduce the suffering from AD. Protoberberine alkaloids isolated from natural resources have previously been reported as potent AChE inhibitors. In order to gain insights into how these alkaloids could inhibit AChE, berberine, palmatine, and cyclanoline were selected to investigate in terms of binding orientation and their key interactions with AChE using molecular docking and molecular dynamics simulations and quantum chemical calculations. The results revealed that the molecular dynamics structures of palmatine and berberine indicated that their equilibrated structures did not occupy the gorge but they slightly moved away from the catalytic site (CAS). For cyclanoline, the binding mode was quite different from those of donepezil and the other protoberberine alkaloids: it preferred to stay deeper in the CAS site. Interaction energies and residual interaction energies confirmed that the key interactions for palmatine and berberine were π-π interactions with Trp286 and Tyr341 and H-bond interactions with Tyr124. Cyclanoline formed π-π interactions with Trp86 and H-bonds to the amino acids in the CAS site. The results suggested the importance of aromaticity in the core structure and the flexibility of the core structure or the substituents in order to fit into the narrow gorge. The HOMO, LUMO, bioavailability, drug-likeness and pharmacokinetics were also predicted. The results obtained will be useful for further AD drug development.
乙酰胆碱酯酶（AChE）在阿尔茨海默病（AD）中起着至关重要的作用，AD 是痴呆症最常见的原因之一。发现新的有效 AChE 活性抑制剂被认为是减少 AD 患者痛苦的有效方法之一。从天然资源中分离出的原小檗碱生物碱以前被报道为有效的 AChE 抑制剂。为了深入了解这些生物碱如何抑制 AChE，选择小檗碱、巴马汀和小檗胺来研究它们与 AChE 的结合取向及其关键相互作用，使用分子对接和分子动力学模拟和量子化学计算。结果表明，巴马汀和小檗碱的分子动力学结构表明，它们的平衡结构不占据峡谷，而是稍微远离催化位点（CAS）。对于小檗胺，结合模式与多奈哌齐和其他原小檗碱生物碱完全不同：它更喜欢停留在 CAS 位点更深的地方。相互作用能和残相互作用能证实，巴马汀和小檗碱的关键相互作用是与 Trp286 和 Tyr341 的π-π相互作用以及与 Tyr124 的氢键相互作用。小檗胺与 Trp86 形成 π-π 相互作用，并与 CAS 位点的氨基酸形成氢键。结果表明，核心结构的芳香性以及核心结构或取代基的灵活性对于适应狭窄的峡谷非常重要。还预测了 HOMO、LUMO、生物利用度、类药性和药代动力学。获得的结果将有助于进一步开发 AD 药物。
