Neurodegenerative disorders (NDDs) are known to exhibit genetic overlap and shared pathophysiology. This study aims to find the shared genetic architecture of Alzheimer's disease (AD) and Parkinson's disease (PD), two major age-related progressive neurodegenerative disorders. The gene expression profiles of GSE67333 (containing samples from AD patients) and GSE114517 (containing samples from PD patients) were retrieved from the Gene Expression Omnibus (GEO) functional genomics database managed by the National Center for Biotechnology Information. The web application GREIN (GEO RNA-seq Experiments Interactive Navigator) was used to identify differentially expressed genes (DEGs). A total of 617 DEGs (239 upregulated and 379 downregulated) were identified from the GSE67333 dataset. Likewise, 723 DEGs (378 upregulated and 344 downregulated) were identified from the GSE114517 dataset. The protein-protein interaction networks of the DEGs were constructed, and the top 50 hub genes were identified from the network of the respective dataset. Of the four common hub genes between two datasets, C-X-C chemokine receptor type 4 (CXCR4) was selected due to its gene expression signature profile and the same direction of differential expression between the two datasets. Mavorixafor was chosen as the reference drug due to its known inhibitory activity against CXCR4 and its ability to cross the blood-brain barrier. Molecular docking and molecular dynamics simulation of 51 molecules having structural similarity with Mavorixafor was performed to find two novel molecules, ZINC49067615 and ZINC103242147. This preliminary study might help predict molecular targets and diagnostic markers for treating Alzheimer's and Parkinson's diseases. Insight Box Our research substantiates the therapeutic relevance of CXCR4 inhibitors for the treatment of Alzheimer's and Parkinson's diseases. We would like to disclose the following insights about this study. We found common signatures between Alzheimer's and Parkinson's diseases at transcriptional levels by analyzing mRNA sequencing data. These signatures were used to identify putative therapeutic agents for these diseases through computational analysis. Thus, we proposed two novel compounds, ZINC49067615 and ZINC103242147, that were stable, showed a strong affinity with CXCR4, and exhibited good pharmacokinetic properties. The interaction of these compounds with major residues of CXCR4 has also been described.

中文翻译：

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初步研究确定 CXCR4 抑制剂作为阿尔茨海默病和帕金森病的潜在治疗药物。

众所周知，神经退行性疾病（NDD）表现出遗传重叠和共同的病理生理学。本研究旨在寻找阿尔茨海默病（AD）和帕金森病（PD）这两种主要的与年龄相关的进行性神经退行性疾病的共同遗传结构。GSE67333（包含来自AD患者的样本）和GSE114517（包含来自PD患者的样本）的基因表达谱是从国家生物技术信息中心管理的基因表达综合（GEO）功能基因组数据库中检索的。网络应用程序 GREIN（GEO RNA-seq Experiments Interactive Navigator）用于识别差异表达基因（DEG）。从 GSE67333 数据集中鉴定出总共 617 个 DEG（239 个上调和 379 个下调）。同样，从 GSE114517 数据集中识别出 723 个 DEG（378 个上调和 344 个下调）。构建了 DEG 的蛋白质-蛋白质相互作用网络，并从各自数据集的网络中识别出前 50 个枢纽基因。在两个数据集之间的四个常见枢纽基因中，选择了 CXC 趋化因子受体 4 型 (CXCR4)，因为它的基因表达特征谱以及两个数据集之间差异表达的相同方向。Mavorixafor 因其已知的 CXCR4 抑制活性及其穿过血脑屏障的能力而被选为参考药物。对51个与Mavorixafor结构相似的分子进行分子对接和分子动力学模拟，发现两个新分子ZINC49067615和ZINC103242147。这项初步研究可能有助于预测治疗阿尔茨海默病和帕金森病的分子靶点和诊断标记。Insight Box 我们的研究证实了 CXCR4 抑制剂对于治疗阿尔茨海默病和帕金森病的治疗相关性。我们想透露有关这项研究的以下见解。通过分析 mRNA 测序数据，我们发现了阿尔茨海默病和帕金森病在转录水平上的共同特征。这些特征用于通过计算分析来识别这些疾病的假定治疗剂。因此，我们提出了两种新化合物，ZINC49067615和ZINC103242147，它们稳定，与CXCR4表现出很强的亲和力，并表现出良好的药代动力学特性。还描述了这些化合物与 CXCR4 主要残基的相互作用。