Systematic identification of molecular biomarkers and drug candidates targeting MAPK3 in multiple sclerosis

Multiple sclerosis (MS) exists as a persistent autoimmune illness affecting the central nervous system because it produces demyelination and injures axons, besides causing CNS neuroinflammation. Research advances into MS pathophysiology have not solved the complexity of treating this condition. The research examined both vital MS-related molecular biomarkers as well as therapeutic possibilities through computational methods. GEO2R analyzed the gene expression dataset GSE17393, which reported that MS patients had differentially expressed genes than healthy controls. The biological processes involved in MS became clearer with the help of functional enrichment analyses, which contained both GO and KEGG pathway analysis. The STRING database enabled the construction of a PPI network, followed by hub gene identification through the CytoHubba application. The study revealed MAPK3 as the most influential hub gene essential for MS pathophysiological processes. Scientists used the Robetta server to forecast MAPK3's 3D structure, which they then optimized in Galaxy Refine before carrying out structural quality tests. Lab simulation using PyRx showed that potential medications such as Hypericin, Yibeissine, and Physalin F effectively bind with the MAPK3 protein. Among the compounds, Hypericin achieved the best binding affinity of −10.7 kcal/mol toward MAPK3, as Yibeissine and Physalin F reached −10.0 kcal/mol binding levels. MD simulations tested the stability of all MAPK3-ligand complex structures. The combination of ADME testing demonstrated that Yibeissine possessed ideal drug absorption features with strong blood-brain barrier penetration alongside good gastrointestinal absorption, yet Hypericin showed poor oral availability. The ProTox-II analysis revealed that the substance Hypericin presented major risks for mutation and cancer development, although Physalin F significantly damaged the human immune system. Current research indicates MAPK3 inhibition represents a promising treatment approach for MS, since Yibeissine stands out as the best drug candidate because it possesses an ideal ADME profile and low toxicity risks.