Preliminary study to identify CXCR4 inhibitors as potential therapeutic agents for Alzheimer's and Parkinson's diseases.

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.