Hu Xia-Min, Dong Wei, Cui Zhi-Wen, Gao Cheng-Zhi, Yu Zhi-Jun, Yuan Qiong, Min Zhen-Li
College of Pharmacy, Shanghai University of Medicine & Health Sciences, Shanghai, China.
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China.
J Mol Model. 2018 Jun 5;24(7):151. doi: 10.1007/s00894-018-3696-6.
Alzheimer's disease (AD) is a chronic neurodegenerative disease of the elderly that seriously affects the quality of life and the life expectancy of those affected. There is, as yet, no effective drug treatment of AD, although several acetylcholinesterase (AChE) inhibitors and a glutamate antagonist can provide relief from its symptoms. Recent studies have indicated that the overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) may promote nerve cell death in the brains of AD patients, implying that PARP-1 inhibition may have therapeutic value for the treatment of AD. Therefore, it is important to investigate novel agents with both AChE- and PARP-1-inhibitory bioactivities. In this study, the structure-based virtual screening of PARP-1 inhibitors was performed to search for potential agents with high affinities for AChE. The dynamic stability of the selected AChE-ligand complexes was investigated by molecular dynamics (MD) simulation. Two compounds, CID57390505 and CID71605390, showed high affinities for and stability in complex with AChE in docking and MD simulations. Thus, our in silico research identified two compounds with AChE and PARP-1 dual-targeted activities, indicating that this technique could aid attempts to develop more potent agents against AD.
阿尔茨海默病（AD）是一种影响老年人的慢性神经退行性疾病，严重影响患者的生活质量和预期寿命。尽管几种乙酰胆碱酯酶（AChE）抑制剂和一种谷氨酸拮抗剂可以缓解其症状，但目前尚无有效的AD药物治疗方法。最近的研究表明，聚（ADP-核糖）聚合酶-1（PARP-1）的过度激活可能会促进AD患者大脑中的神经细胞死亡，这意味着抑制PARP-1可能对AD治疗具有治疗价值。因此，研究具有AChE和PARP-1抑制生物活性的新型药物非常重要。在本研究中，进行了基于结构的PARP-1抑制剂虚拟筛选，以寻找对AChE具有高亲和力的潜在药物。通过分子动力学（MD）模拟研究了所选AChE-配体复合物的动态稳定性。在对接和MD模拟中，两种化合物CID57390505和CID71605390对AChE具有高亲和力且在与AChE形成复合物时具有稳定性。因此，我们的计算机模拟研究确定了两种具有AChE和PARP-1双靶点活性的化合物，表明该技术有助于开发更有效的抗AD药物。
