Targeting Hub Genes in Spinocerebellar Ataxia type 2: An Genomics and Molecular Dynamics Approach to Drug Discovery

Spinocerebellar ataxia Type 2 (SCA2) is a progressive brain disorder that impacts movement and coordination, primarily due to genetic mutations. This study employed computational techniques to identify potential treatment targets for SCA2. Gene expression data from GEO datasets (GSE189417, GSE151276, GSE200530) were analyzed to identify genes that displayed increased activity in SCA2 patients. Genes with a fold change (FC) greater than 1.2 and a p-value of less than 0.05 were chosen. A network of interacting proteins was subsequently constructed using STRING, where key genes, Epidermal Growth Factor Receptor (EGFR) and Interleukin-6 (IL6), were recognized through the CytoHubba plugin in Cytoscape. An additional biological function analysis was conducted using Gene Ontology and KEGG pathway analyses to enhance the understanding of the processes related to SCA2. The structures of these key genes were examined, and their active sites were mapped. A total of 100 natural compounds known for their neuroprotective effects were assessed through molecular docking. Among these, Withaferin A emerged as the most promising candidate, demonstrating strong binding to EGFR (−11.6 kcal/mol) and IL6 (−9.4 kcal/mol). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of Withaferin A were evaluated, confirming its high absorption in the gastrointestinal tract, and non-toxic nature. To further assess its effectiveness and stability, molecular dynamics simulations were conducted for 100 ns, indicating stability. The interactions between Withaferin A and the target proteins (EGFR and IL6) were found to be stable, with minimal structural fluctuations and favorable binding free energy. Based on these findings, it is suggested that Withaferin A may represent a promising therapeutic option for SCA2 by targeting EGFR and IL6. However, further in vivo and in vitro studies are necessary to verify its potential effectiveness for clinical use.