Şahİn Kader, DurdaĞi Serdar
Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahçeşehir University, Istanbul Turkey.
Turk J Chem. 2020 Jun 1;44(3):574-588. doi: 10.3906/kim-1911-57. eCollection 2020.
The excessive activity of acetylcholinesterase enzyme (AChE) causes different neuronal problems, especially dementia and neuronal cell deaths. Food and Drug Administration (FDA) approved drugs donepezil, rivastigmine, tacrine and galantamine are AChE inhibitors and in the treatment of Alzheimer's disease (AD) these drugs are currently prescribed. However, these inhibitors have various adverse side effects. Therefore, there is a great need for the novel selective AChE inhibitors with fewer adverse side effects for the effective treatment. In this study, combined ligand-based and structure-based virtual screening approaches were used to identify new hit compounds from small molecules library of National Cancer Institute (NCI) containing approximately 265,000 small molecules. In the present study, we developed a computational pipeline method to predict the binding affinities of the studied compounds at the specific target sites. For this purpose, a text mining study was carried out initially and compounds containing the keyword "indol" were considered. The therapeutic activity values against AD were screened using the binary quantitative structure activity relationship (QSAR) models. We then performed docking, molecular dynamics (MD) simulations and free energy analysis to clarify the interactions between selected ligands and enzyme. Thus, in this study we identified new promising hit compounds from a large database that may be used to inhibit the enzyme activity of AChE.
乙酰胆碱酯酶（AChE）的过度活性会引发不同的神经元问题，尤其是痴呆和神经元细胞死亡。美国食品药品监督管理局（FDA）批准的药物多奈哌齐、卡巴拉汀、他克林和加兰他敏是AChE抑制剂，目前在治疗阿尔茨海默病（AD）时会使用这些药物。然而，这些抑制剂有各种不良副作用。因此，迫切需要新型选择性AChE抑制剂，其副作用更少，以便进行有效治疗。在本研究中，结合基于配体和基于结构的虚拟筛选方法，从美国国立癌症研究所（NCI）包含约265,000个小分子的小分子库中鉴定新的命中化合物。在本研究中，我们开发了一种计算管道方法来预测所研究化合物在特定靶位点的结合亲和力。为此，首先进行了一项文本挖掘研究，并考虑了包含关键词“吲哚”的化合物。使用二元定量构效关系（QSAR）模型筛选针对AD的治疗活性值。然后我们进行对接、分子动力学（MD）模拟和自由能分析，以阐明所选配体与酶之间的相互作用。因此，在本研究中，我们从一个大型数据库中鉴定出了新的有前景的命中化合物，这些化合物可用于抑制AChE的酶活性。
