In silico drug repositioning for the treatment of Alzheimer's disease using molecular docking and gene expression data
In silico drug repositioning for the treatment of Alzheimer's disease using molecular docking and gene expression data
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使用分子对接和基因表达数据进行计算机药物重新定位以治疗阿尔茨海默病
DOI：
10.1039/c6ra21941a
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发表时间：
2016-10
期刊：
影响因子：
3.9
通讯作者：
Chen Xiujie
中科院分区：
文献类型：
--
作者：
Xie Hongbo;Wen Haixia;Qin Mingze;Xia Jie;Zhang Denan;Liu Lei;Liu Bo;Liu Qiuqi;Jin Qing;Chen Xiujie
阿尔茨海默病（AD）是一种影响老年人的多因素神经退行性疾病。尽管这种疾病的破坏性影响，治疗AD的治疗方法仍然有限，因为许多因素导致其病因。近几十年来，已经开发了许多小分子和生物制品用于治疗AD;然而，仍然没有产生有效的疾病修饰作用的药物。药物重新定位是药物发现的另一种方法，因为许多有效的药物通过调节多个靶点起作用，这种“多药理学”可能是复杂疾病的治疗要求。AD的多因素性质强烈支持以药物重新定位为中心的药物设计策略的基本原理。本研究采用基于配体-蛋白质反向对接和基因表达数据挖掘的计算流水线技术，探索治疗AD的潜在药物。我们对1553种FDA批准的药物进行了7种主要AD药物靶点的虚拟筛选。几种药物显示出极高的结合自由能的七个目标。此外，基因表达数据是一个非常丰富的替代资源，用于推断药物和基因之间的非明显关系。响应于所鉴定的药物的基因表达谱支持对接结果，并提供了与AD患者中药物结合的蛋白质响应相关的途径的合理视角。这些结果导致发现氟哌利多、格列美脲、利培酮和其他FDA批准的药物作为治疗AD的潜在多靶点候选药物。
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that affects the elderly. Despite the devastating effects of this disease, therapeutic methods for the treatment of AD remain limited, as many factors contribute to its etiology. In recent decades, many small molecules and bioproducts have been developed for the treatment of AD; however, there are still no drugs that produce efficient disease-modifying effects. Drug repositioning is an alternative methodology for drug discovery because many effective drugs act via the modulation of multiple targets, and this ‘poly-pharmacology’ can be a therapeutic requirement for complex diseases. The multifactorial nature of AD strongly supports the rationale for a drug design strategy centered on drug repositioning. In this study, a computational pipeline based on ligand–protein inverse docking and gene expression data mining were adopted to explore potential drugs for the treatment of AD. We performed a virtual screening of 1553 FDA-approved drugs on seven major AD drug targets. Several drugs showed extremely high binding free energies for the seven targets. Furthermore, gene expression data represent a very rich alternative resource for inferring non-obvious relationships between drugs and genes. The gene expression profiles in response to the identified drugs support the docking results and offer a plausible perspective on the pathways associated with protein responses to drug binding in AD patients. The results have led to the discovery of droperidol, glimepiride, risperidone and other FDA-approved drugs as potential multi-target candidates for the treatment of AD.
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DOI：
10.1038/nrd2030
发表时间：
2006-08
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Ghofrani HA;Osterloh IH;Grimminger F
通讯作者：
Grimminger F
影响因子：
3.4
作者：
Hitesh Patel;X. Lucas;I. Bendik;S. Günther;I. Merfort
通讯作者：
Hitesh Patel;X. Lucas;I. Bendik;S. Günther;I. Merfort
影响因子：
4.3
作者：
Yang L;Wang K;Chen J;Jegga AG;Luo H;Shi L;Wan C;Guo X;Qin S;He G;Feng G;He L
通讯作者：
He L
影响因子：
3.4
作者：
Riederer, P;Danielczyk, W;Grünblatt, E
通讯作者：
Grünblatt, E
DOI：
10.1016/s0093-3619(08)70659-2
发表时间：
2007
期刊：
Yearbook of Dermatology and Dermatologic Surgery
影响因子：
--
作者：
B. Thiers
通讯作者：
B. Thiers