Comparative Target and Mechanistic Profiling of Lycopene and Primidone in Traumatic Brain Injury: A Network Pharmacology and Molecular Docking Study

Abstract

Background: There is no approved disease-modifying drug for traumatic brain injury (TBI). The secondary
injury that follows the impact is not a single pathway but a set of linked inflammatory, oxidative and cellular
processes. A drug combination is more likely to help when the two agents act on different parts of that network
rather than the same part. This study compared the predicted target profiles of lycopene and primidone in TBI
using network pharmacology and molecular docking.
Methods: Putative targets of both compounds were predicted in SwissTargetPrediction, broadened in
GeneCards and standardised in UniProt. These were intersected with TBI-associated genes from GeneCards
and OMIM. The observed overlap was tested against a hypergeometric null model. The shared targets were
assembled into a STRING protein–protein interaction network, ranked by node degree, and analysed for
functional enrichment in DAVID. Both compounds were then docked into the ten highest-ranking hub proteins
using AutoDock Vina.
Results: Lycopene returned 269 predicted targets and primidone 175, of which 210 and 138 were TBI-
associated. Of the 326 combined targets, 93.3% belonged to one compound only. The 22 shared targets were
4.6-fold more numerous than chance expectation (P = 1.3 × 10⁻⁹), and 21 of them formed a single connected
module. That module was enriched for inflammatory response, reactive oxygen species metabolism, membrane
raft and axolemmal localisation, and heme binding. Both compounds showed predicted interactions with all
ten hub proteins. Across nine matched pockets, lycopene gave the more negative predicted affinity at every
target, while primidone gave the higher ligand efficiency at every target (0.299 against 0.215 kcal/mol per
heavy atom; Wilcoxon P = 0.004).
Conclusion: Lycopene and primidone act on largely different TBI-associated targets, but meet on a small
inflammatory and heme–redox core. Their docking profiles differ in the same way: one compound binds more
strongly, the other more efficiently. These findings support further experimental work on the two compounds
alone and in combination. They also show that a docking score should not be read on its own, without ligand
efficiency or other measures of molecular size.