Evaluating the neuroprotective potential of and in Huntington's disease: an integrative bioinformatics approach.

Unlabelled: Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by CAG repeat expansion in the HTT gene, leading to oxidative stress, mitochondrial dysfunction, and neuroinflammation. Conventional therapies offer only symptomatic relief with limited efficacy. This study aimed to explore the neuroprotective potential of (MP) and (BS) through an integrative bioinformatics approach, targeting multiple pathological mechanisms implicated in HD. Phytoconstituents from MP and BS were selected based on pharmacokinetic properties, including drug-likeness and blood-brain barrier permeability. Differential gene expression analysis was performed using GEO datasets to identify HD-related genes. Target prediction, network pharmacology, protein-protein interaction (PPI) network construction, and pathway enrichment analyses were carried out. Key proteins were subjected to molecular docking using AutoDock Vina and stability was evaluated through molecular dynamics simulations. A total of 47 phytoconstituents were identified, associated with 1333 (MP) and 693 (BS) potential targets. Network pharmacology revealed the involvement of PI3K-Akt, MAPK, NF-kappa B, and neurotrophin signaling pathways. AKT1, MAPK1, and SLC6A3 emerged as central hub proteins. Molecular docking demonstrated strong binding affinities of levodopa, tyrosine, and phenylalanine with core HD-related proteins (AKT1, EGFR, and SLC6A3). Molecular dynamics simulations further confirmed complex stability, with RMSD values ranging between 1.8 and 3.2 Å across key ligand-protein pairs supporting their neuroprotective potential. This integrative bioinformatics analysis highlights that phytoconstituents from and modulate key molecular pathways involved in HD pathogenesis. MP exhibited antioxidative and dopamine-enhancing effects, while BS showed significant anti-inflammatory effects. These findings suggest that MP and BS may serve as promising plant-based therapeutic candidates for HD, warranting further in vitro and in vivo validation.

Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00398-2.