Akili Abd Wahid Rizaldi, Thurfah Nisrina Azizah, Hardianto Ari, Latip Jalifah, Herlina Tati
Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia.
Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi, Selangor, 46300, Malaysia.
Adv Appl Bioinform Chem. 2024 Nov 1;17:107-118. doi: 10.2147/AABC.S483115. eCollection 2024.
This study aimed to evaluate the potency of 471 flavonoids from the genus as potential acetylcholinesterase (AChE) inhibitors and free radical scavengers through computational studies to develop Alzheimer's disease (AD) therapies from natural products.
A total of 471 flavonoids from the genus were subjected to molecular docking against AChE, followed by toxicity screening. The potential AChE inhibitors with the least toxic profile were subjected to further investigation through molecular dynamics (MD) simulations, density functional theory (DFT) study, and in silico pharmacokinetic predictions.
A combination of molecular docking and in silico toxicity screening led to the identification of 2(S)‒5,7‒dihydroxy‒5'‒methoxy‒[2'',2''‒(3''‒hydroxy)‒dimethylpyrano]‒(5'',6'':3',4') flavanone (89) and Abyssinoflavanone IV (83) as potential AChE inhibitors. These compounds had stable binding to AchE and exhibited lower Root Mean Square Deviation (RMSD) values compared to the apo state of AChE. In addition, Molecular Mechanics Generalized Born Surface Area (MMGBSA) analysis revealed that the binding energies of 89 and 83 were significantly lower compared to acetylcholine, the natural substrate of AChE. Based on DFT study, these compounds exhibited a higher energy in the highest occupied molecular orbital (E) and lower electron affinity (EA) than Quercetin. This indicated that 89 and 83 could be potential radical scavengers through their electron-donating activity.
Although this study primarily relied on computational methods, the results showed the dual functionality of compounds 89 and 83 as both potential AChE inhibitors and free radical scavengers. Further investigation in wet laboratory experiments is required to validate their therapeutic potential for AD.
本研究旨在通过计算研究评估该属471种黄酮类化合物作为潜在乙酰胆碱酯酶（AChE）抑制剂和自由基清除剂的效力，以便从天然产物开发阿尔茨海默病（AD）疗法。
对该属的471种黄酮类化合物进行AChE分子对接，随后进行毒性筛选。对毒性最小的潜在AChE抑制剂通过分子动力学（MD）模拟、密度泛函理论（DFT）研究和计算机模拟药代动力学预测进行进一步研究。
分子对接和计算机模拟毒性筛选相结合，鉴定出2(S)-5,7-二羟基-5'-甲氧基-[2'',2''-(3''-羟基)-二甲基吡喃]- (5'',6'':3',4') 黄烷酮（89）和阿比西尼亚黄酮IV（83）为潜在AChE抑制剂。这些化合物与AChE具有稳定结合，与AChE的无配体状态相比，表现出更低的均方根偏差（RMSD）值。此外，分子力学广义玻恩表面积（MMGBSA）分析表明，与AChE的天然底物乙酰胆碱相比，89和83的结合能显著更低。基于DFT研究，这些化合物在最高占据分子轨道（E）中的能量高于槲皮素，电子亲和力（EA）低于槲皮素。这表明89和83可通过其供电子活性成为潜在的自由基清除剂。
尽管本研究主要依赖计算方法，但结果显示化合物89和83具有作为潜在AChE抑制剂和自由基清除剂的双重功能。需要在湿实验室实验中进行进一步研究以验证它们对AD的治疗潜力。
