University Mohamed Khider, Department of Matter Sciences, BP 145 RP, 07000, Biskra, Algeria; Laboratory of Natural and bio-actives Substances, Tlemcen University, Faculty of Science, P.O. Box 119, Tlemcen, Algeria.
Group of Computational and Pharmaceutical Chemistry LMCE Laboratory, University of Biskra, 07000, Algeria.
Comput Biol Chem. 2018 Jun;74:304-326. doi: 10.1016/j.compbiolchem.2018.03.021. Epub 2018 Mar 29.
This work deals with several molecular modeling methods used to discover new therapeutic agents for treating the Alzheimer's disease (AD). The cholinergic hypothesis was initially presented over 30 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain. Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) are of the keys targets of drugs for treating AD.
QSAR, Molecular Docking/Dynamics and ADME properties were carried out in order to study 36 compounds that belong to the 4-[(diethylamino)methyl]-phenol derivatives and test their AChE and BuChE inhibitory activities, MOE, HyperChem and others softwares were used to find the best compounds with high affinity.
The QSAR models exhibited good statistical values for both targets AChE (R = 0.660, q = 0.70, F-ratio = 18.008) and BuChE (R = 0.726, q = 0.75, F-ratio = 31.864). The interactions between the studied inhibitors and our targets were further explored through molecular docking and molecular dynamics simulations. A few key residues (TRP279, TYR334, PHE330 and TRP84) at the binding site of AChE and key residues (HIS438, TYR332, PHE329 and TRP82) at the binding site of BuChE were identified.
Based on this study compounds 23 and 28 have no violated Lipinski's rule of five and thus, showing the possibility of being potential candidates for further studies in drug development process against the AChE and BuChE targets respectively.
本研究采用多种分子建模方法，旨在发现治疗阿尔茨海默病（AD）的新治疗药物。胆碱能假说最初是在 30 多年前提出的，它表明大脑中含有乙酰胆碱的神经元功能失调。乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）是治疗 AD 药物的关键靶标。
为了研究 36 种属于 4-[(二乙氨基)甲基]苯酚衍生物的化合物，并测试它们对 AChE 和 BuChE 的抑制活性，进行了 QSAR、分子对接/动力学和 ADME 性质研究。使用 MOE、HyperChem 等软件寻找具有高亲和力的最佳化合物。
QSAR 模型对 AChE（R=0.660，q=0.70，F-比=18.008）和 BuChE（R=0.726，q=0.75，F-比=31.864）两个靶标均显示出良好的统计值。通过分子对接和分子动力学模拟进一步研究了研究抑制剂与我们靶标的相互作用。在 AChE 的结合部位鉴定出几个关键残基（TRP279、TYR334、PHE330 和 TRP84）和 BuChE 的结合部位的关键残基（HIS438、TYR332、PHE329 和 TRP82）。
基于这项研究，化合物 23 和 28 均不违反 Lipinski 的五规则，因此有可能分别成为进一步研究开发针对 AChE 和 BuChE 靶标的潜在候选药物。
