SIRT1 Emerges as a Convergent Target of Primidone in Traumatic Brain Injury: A Network Pharmacology and Molecular Docking Study

Abstract

Purpose: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, and no disease-modifying pharmacological therapy has yet received regulatory approval. Drug repurposing offers a rapid route to bridge this gap. Primidone, a clinically established barbiturate anticonvulsant, remains largely unexplored in TBI despite evidence that it may exert neuroprotective actions beyond seizure suppression. This study used an integrative in silico framework to evaluate primidone's therapeutic relevance in TBI.
Materials and Methods: Primidone-associated targets were identified using SwissTargetPrediction and GeneCards, and TBI-associated genes were retrieved from the Online Mendelian Inheritance in Man (OMIM) database and GeneCards. Intersecting these datasets yielded 138 overlapping targets, which were mapped onto a protein–protein interaction (PPI) network in STRING and analyzed in Cytoscape. Hub genes were prioritized using the CytoHubba maximum clique centrality (MCC) algorithm, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses defined the biological processes and pathways engaged by these targets. Molecular docking using AutoDock Vina then evaluated primidone's binding affinity toward the prioritized hub proteins to validate the network-predicted interactions structurally.
Results: Network analysis identified ALB, JUN, PTGS2, CASP3, MMP9, CXCL8, HMOX1, APP, CYP2E1, and SIRT1 as the top ten hub genes, linking primidone to neuroinflammation, oxidative stress, apoptosis, and extracellular matrix remodeling. KEGG enrichment mapped these targets to apoptosis, NF-κB, PI3K-Akt, MAPK, and oxidative stress-response pathways. Molecular docking showed the strongest predicted affinity toward SIRT1 (−9.0 kcal/mol), followed by JUN (−6.8 kcal/mol) and MMP9 (−5.9 kcal/mol), with weaker affinities across the remaining hub proteins (−5.5 to −2.4 kcal/mol; Table 3). This ranking indicates that primidone's predicted interactions converge most strongly on SIRT1-mediated oxidative-stress regulation, with secondary, lower-affinity engagement spanning inflammatory, apoptotic, and extracellular-matrix pathways.
Conclusion: This systems-level analysis identifies primidone as a promising repurposing candidate for TBI, converging on a molecular network centered on SIRT1-mediated oxidative-stress regulation, alongside apoptotic and neuroinflammatory signaling. Given its established clinical safety profile, primidone holds translational potential as a repurposed neuroprotective intervention in TBI, warranting further preclinical and clinical evaluation.