Arif Nadia, Subhani Andleeb, Hussain Waqar, Rasool Nouman
Department of Life Sciences, University of Management and Technology, Lahore 54770, Pakistan
National Center of Artificial Intelligence, Punjab University College of Information Technology, University of the Punjab, Lahore, Pakistan
Curr Drug Discov Technol. 2020;17(3):397-411. doi: 10.2174/1570163816666190214161825.
Alzheimer's Disease (AD) has become the most common age-dependent disease of dementia. The trademark pathologies of AD are the presence of amyloid aggregates in neurofibrils. Recently phytochemicals being considered as potential inhibitors against various neurodegenerative, antifungal, antibacterial and antiviral diseases in human beings.
This study targets the inhibition of BACE-1 by phytochemicals using in silico drug discovery analysis.
A total of 3150 phytochemicals were collected from almost 25 different plants through literature assessment. The ADMET studies, molecular docking and density functional theory (DFT) based analysis were performed to analyze the potential inhibitory properties of these phytochemicals.
The ADMET and docking results exposed seven compounds that have high potential as an inhibitory agent against BACE-1 and show binding affinity >8.0 kcal/mol against BACE-1. They show binding affinity greater than those of various previously reported inhibitors of BACE-1. Furthermore, DFT based analysis has shown high reactivity for these seven phytochemicals in the binding pocket of BACE- 1, based on ELUMO, EHOMO and Kohn-Sham energy gap. All seven phytochemicals were testified (as compared to experimental ones) as novel inhibitors against BACE-1.
Out of seven phytochemicals, four were obtained from plant Glycyrrhiza glabra i.e. Shinflavanone, Glabrolide, Glabrol and PrenyllicoflavoneA, one from Huperzia serrate i.e. Macleanine, one from Uncaria rhynchophylla i.e. 3a-dihydro-cadambine and another one was from VolvalerelactoneB from plant Valeriana-officinalis. It is concluded that these phytochemicals are suitable candidates for drug/inhibitor against BACE-1, and can be administered to humans after experimental validation through in vitro and in vivo trials.
阿尔茨海默病（AD）已成为最常见的年龄相关性痴呆疾病。AD的标志性病理特征是神经原纤维中存在淀粉样蛋白聚集体。最近，植物化学物质被认为是针对人类各种神经退行性疾病、抗真菌、抗菌和抗病毒疾病的潜在抑制剂。
本研究旨在通过计算机辅助药物发现分析，利用植物化学物质抑制β-分泌酶1（BACE-1）。
通过文献评估从近25种不同植物中收集了总共3150种植物化学物质。进行了药物代谢及毒性研究（ADMET）、分子对接和基于密度泛函理论（DFT）的分析，以分析这些植物化学物质的潜在抑制特性。
ADMET和对接结果显示，有7种化合物具有作为BACE-1抑制剂的高潜力，并且对BACE-1的结合亲和力>8.0千卡/摩尔。它们的结合亲和力高于先前报道的各种BACE-1抑制剂。此外，基于DFT的分析表明，基于最低未占据分子轨道（ELUMO）、最高占据分子轨道（EHOMO）和科恩-沈（Kohn-Sham）能隙，这7种植物化学物质在BACE-1的结合口袋中具有高反应活性。所有7种植物化学物质均被证明（与实验结果相比）是针对BACE-1的新型抑制剂。
在这7种植物化学物质中，4种来自甘草（Glycyrrhiza glabra），即新黄酮、光甘草内酯、光甘草定和异戊烯基异黄酮A；1种来自蛇足石杉（Huperzia serrata），即迈立胺；1种来自钩藤（Uncaria rhynchophylla），即3a-二氢-卡丹宾；另1种来自缬草（Valeriana-officinalis）的缬草环烯醚萜B。得出结论，这些植物化学物质是针对BACE-1的药物/抑制剂的合适候选物，并且在通过体外和体内试验进行实验验证后可用于人类。
