Abstract：
Alzheimer\'s disease (AD) is the most common cause of dementia worldwide and is classified as a neurodegenerative disorder. From a drug design perspective, natural products (NPs) are more drug-like and are highly compatible with biological systems compared to most synthetic libraries. NPs provide a more efficient and cost-effective approach to new drug discovery. However, the complexity of NPs makes their identification a challenging task. Chimgin, a bicyclic monoterpene with three chiral centers, exhibits a wide range of biological activity. Despite this, the exact structure of chimgin has remained unclear until now. In this study, we quantified the amount of chimgin in Ferula haussknechtii using analytical Reversed-phase high-pressure liquid chromatography equipped with photodiode array detector (RP-HPLC-PDA). Furthermore, we determined the absolute configuration of chimgin through electronic circular dichroism (ECD) spectroscopy and time-dependent density functional theory (TDDFT) calculations. Finally, we evaluated its inhibitory effect on AChE through in vitro and in silico studies. The extraction process yielded an output of 2.82 ± 0.10% with an exact amount of 0.62 ± 0.04 mg of chimgin per 100 g of plant. Based on the results of ECD and TDDFT calculation, the absolute configuration of chimgin was determined to be 1S, 2S, 4S. Chimgin exhibited an inhibitory effect on AChE with an IC50 of 37.43 µM and its mechanism of action was found to be competitive. HighlightsChimgin was isolated from the roots of Ferula haussknechtii.The amount of chimgin in the plant was determined by RP-HPLC-PDA.Its absolute configuration of chimgin was determined using ECD.In vitro acetylcholinesterase activity of the chimgin was evaluated.The docking and molecular dynamic simulation of chimgin was done.Communicated by Ramaswamy H. Sarma.
摘要：
阿尔茨海默病（AD）是世界范围内痴呆的最常见原因，被归类为神经退行性疾病。从药物设计的角度来看，与大多数合成库相比,天然产物(NPs)更像药物,并且与生物系统高度兼容.NP为新药发现提供了更有效和更具成本效益的方法。然而,NP的复杂性使其识别成为一项具有挑战性的任务。嵌合体,具有三个手性中心的双环单萜，具有广泛的生物活性。尽管如此,到目前为止，黑猩猩的确切结构仍不清楚。在这项研究中,我们使用配备光电二极管阵列检测器的分析反相高压液相色谱法（RP-HPLC-PDA）定量了Ferulahaussknechtii中的嵌合体含量。此外，我们通过电子圆二色性（ECD）光谱和时间依赖性密度泛函理论（TDDFT）计算确定了黑猩猩的绝对构型。最后,我们通过体外和计算机模拟研究评估了其对AChE的抑制作用。提取过程的产量为2.82±0.10％，每100克植物的确切数量为0.62±0.04mg。根据ECD和TDDFT计算结果，黑猩猩的绝对构型被确定为1S，2S,4S。嵌合体对AChE表现出抑制作用，IC50为37.43µM，发现其作用机制具有竞争性。HighlightsChimgin是从Ferulahaussknechtii的根中分离出来的。通过RP-HPLC-PDA测定植物中的嵌合体的量。使用ECD确定其黑猩猩的绝对构型。评估了黑猩猩的体外乙酰胆碱酯酶活性。对黑猩猩进行了对接和分子动力学模拟。由RamaswamyH.Sarma沟通。
