Department of Pharmacy, Shaheed Benazir Bhutto University, Sheringal, Dir (U) 18000, KP, Pakistan.
Department of Chemistry, University of Malakand, Chakdara, Dir (L) 18550, KP, Pakistan.
Fitoterapia. 2022 Oct;162:105268. doi: 10.1016/j.fitote.2022.105268. Epub 2022 Aug 10.
The main objective of our present research work was to explore molecular insight for potentially active new acetylcholinesterase inhibitor from the aerial parts of Delphinium uncinatum. New norditerpenoid alkaloids, uncinatine-A, was isolated from the basic alkaloidal fraction of D. uncinatum, based on bioactivity guided isolation. The structure of uncinatine-A was determined through latest spectroscopic techniques including single X-Ray diffraction technique. The structural data and electronic properties of uncinatine-A was also calculated by Density Functional Theory (DFT) using B3LYP/6-31þ G (p) basis set. The isolated natural product was evaluated for their acetyl cholinesterase inhibitory potential in dose dependent protocol (62.5-1000 μg/mL), followed by molecular docking studies. Significant competitive type inhibition activity (IC 207.73 ± 0.3) was shown by isolated natural norditerpenoid against cholinesterase targets in comparison with standard drugs available in the market such as galanthamine. The molecular docking results showed that isolated natural product was well accommodated by AChE in the active site with docking scores -11.0326. This is the first report indicating uncinatine-A as a potent acetylcholinesterase inhibitor and can be used as a target drug in cerebral dementia and Alzheimer diseases.
本研究工作的主要目的是从蓝盆花的地上部分探索潜在的新型乙酰胆碱酯酶抑制剂的分子特征。根据生物活性导向分离，从蓝盆花的碱性生物碱部分分离出新型北美黄连碱。通过最新的光谱技术，包括单晶 X 射线衍射技术，确定了 uncinatine-A 的结构。还使用密度泛函理论（DFT），通过 B3LYP/6-31þ G（p）基组计算了 uncinatine-A 的结构数据和电子性质。根据剂量依赖方案（62.5-1000μg/mL）评估分离的天然产物对乙酰胆碱酯酶的抑制潜力，然后进行分子对接研究。与市场上可用的标准药物如加兰他敏相比，分离出的天然北美二萜类化合物对胆碱酯酶靶点表现出显著的竞争性抑制活性（IC 20 为 77.73±0.3）。分子对接结果表明，分离出的天然产物与 AChE 在活性部位很好地结合，对接评分为-11.0326。这是首次报道 uncinatine-A 作为一种有效的乙酰胆碱酯酶抑制剂，可以作为治疗痴呆症和阿尔茨海默病的靶标药物。
