Targeting IDO1 in Huntington's Disease: Network Pharmacology and Preclinical Evidence from Coffea arabica

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by involuntary motor dysfunction and progressive cognitive impairment. This study aimed to explore the therapeutic potential of Coffea arabica (CA) phytoconstituents using a network pharmacology-based drug repurposing approach. CA-related Phytoconstituents were identified from public databases, while HD-related targets were retrieved from the DisGeNET database. Indoleamine 2,3-dioxygenase (IDO1) and huntingtin (HTT) were identified as two common overlapping targets using Venny 2.1. Protein-protein interaction (PPI) networks were constructed by CytoScape software. Gene ontology (GO) and KEGG pathway enrichment analysis, followed by MCODE and ClueGO software, revealed IDO1, HTT, PPAR-γ, ESR1, and CASP3 as key targets in HD pathogenesis. Among CA phytoconstituents, geraniol was selected based on its high binding affinity to IDO1 (PDB: 6V52), with a docking score of-8.01 kcal/mol compared to-4.39 kcal/mol for the reference inhibitor. Density functional theory (DFT) analysis showed a dipole moment of 2.50 Debye. Molecular dynamics simulations confirmed the stability of the IDO1-geraniol complex, with key interactions involving Ser167. In a 3-nitropropionic acid (3-NP)-induced HD animal model, geraniol (15 mg/kg) significantly improved motor function and cognitive performance, reduced lipid peroxidation and nitrite levels, and restored the activities of antioxidant enzymes (SOD, GSH, catalase). Neurotransmitter alterations (GABA, DA, glutamate, AChE) were also regulated. Histological studies revealed preservation of striatal neurons. These findings suggest that geraniol exerts neuroprotective effects in HD via modulation of IDO1 activity, oxidative stress, and neurotransmitter balance. SIGNIFICANCE STATEMENT: This study integrates network pharmacology, in silico modeling, and in vivo analysis to explore geraniol, a key metabolite of Coffea arabica, as a multi-target agent for Huntington's disease (HD). Geraniol showed strong binding to IDO1, restored cognitive and motor functions, balanced oxidative stress, and preserved striatal neurons in an HD rat model. Our findings suggest geraniol as a promising therapeutic candidate through modulation of IDO1, redox balance, and neurotransmitters.