Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea.
Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Korea.
Molecules. 2021 Apr 30;26(9):2641. doi: 10.3390/molecules26092641.
Alzheimer's disease (AD) is the most common form of dementia and is characterized by irreversible and progressive neurodegeneration. Cholinergic dysfunction has been reported in AD, and several cholinesterase inhibitors, including natural compounds and synthetic analogs, have been developed to treat the disease. However, there is currently no treatment for AD, as most drug-like compounds have failed in clinical trials. Acetylcholinesterase (AChE) is the target of most drugs used commercially to treat AD. This work focused on screening natural compounds obtained from the ZINC database (224, 205 compounds) against AChE to identify those possibly capable of enabling the management of AD. Indirubin and dehydroevodiamine were the best potential AChE inhibitors with free binding energies of -10.03 and -9.00 kcal/mol, respectively. The key residue (His) of the active site of AChE was found to participate in complex interactions with these two molecules. Six H-bonds were involved in the 'indirubin-AChE' interaction and three H-bonds in the 'dehydroevodiamine-AChE' interaction. These compounds were predicted to cross the blood-brain barrier (BBB) and to exhibit high levels of intestinal absorption. Furthermore, 'indirubin-AChE' and 'dehydroevodiamine-AChE' complexes were found to be stable, as determined by root mean square deviation (RMSD) during a 50 ns molecular dynamics simulation study. Based on the free binding energies and stabilities obtained by simulation studies, we recommend that experimental studies be undertaken on indirubin and dehydroevodiamine with a view towards their potential use as treatments for AD.
阿尔茨海默病（AD）是最常见的痴呆症形式，其特征是不可逆转和进行性的神经退行性变。AD 中报道了胆碱能功能障碍，已经开发了几种乙酰胆碱酯酶抑制剂，包括天然化合物和合成类似物，用于治疗这种疾病。然而，目前还没有治疗 AD 的方法，因为大多数类药化合物在临床试验中都失败了。乙酰胆碱酯酶（AChE）是大多数用于商业治疗 AD 的药物的靶标。这项工作集中在筛选来自 ZINC 数据库（224，205 种化合物）的天然化合物对 AChE 的抑制作用，以鉴定那些可能能够治疗 AD 的化合物。靛玉红和去氢吴茱萸碱是最好的潜在 AChE 抑制剂，其自由结合能分别为-10.03 和-9.00 kcal/mol。发现 AChE 活性位点的关键残基（His）与这两种分子参与复杂相互作用。在“靛玉红-AChE”相互作用中涉及 6 个氢键，在“去氢吴茱萸碱-AChE”相互作用中涉及 3 个氢键。这些化合物被预测能够穿过血脑屏障（BBB）并表现出高水平的肠道吸收。此外，通过 50 ns 分子动力学模拟研究发现“靛玉红-AChE”和“去氢吴茱萸碱-AChE”复合物稳定。基于模拟研究获得的自由结合能和稳定性，我们建议对靛玉红和去氢吴茱萸碱进行实验研究，以期将它们潜在地用于治疗 AD。
