In Silico Analysis of Garcinia kola Secondary Metabolites Targeting Dopamine and Norepinephrine Transporters for ADHD Therapy

Attention-deficit/hyperactivity disorder (ADHD) is a neurological disorder associated with dysregulated dopaminergic and noradrenergic signaling. Although current pharmacotherapies are effective, they carry significant cardiovascular and abuse liabilities, highlighting the need for safer, targeted alternatives. This study evaluated Garcinia kola secondary metabolites as potential inhibitors of human dopamine (DAT) and norepinephrine (NET) transporters utilizing in silico approaches. Of twenty-seven metabolites, sixteen met Lipinski’s Rule-of-Five and synthetic accessibility (SA) criteria and were further analyzed through molecular docking and CNS-relevant ADMET profiling. Cycloartenol, δ-tocotrienol, and 2-hydroxyxanthone demonstrated the strongest predicted dual-target binding affinities with both transporters, surpassing those of the reference ligand, atomoxetine, and engaging targets via hydrophobic, aromatic, and hydrogen-bonding interactions. ADMET analysis indicated that cycloartenol, δ-tocotrienol, and 2-hydroxyxanthone have high predicted brain exposure, favorable bioavailability, and no hepatotoxicity, whereas the reference ligand atomoxetine was flagged for hepatotoxicity. Garcifuran B and Garcipyran also showed favorable dual binding affinities and interactions, compared to the reference ligands, but predicted low blood-brain barrier permeability, suggesting that structural optimization may be required to improve their CNS delivery. In conclusion, δ-tocotrienol, cycloartenol, and 2-hydroxyxanthone emerge as predictive leads for dual DAT/NET inhibition and warrant further experimental in vitro and in vivo validation as safer, non-stimulant ADHD therapeutics.