AI-Guided Network Pharmacology and Neuroimmune Synergy of Peganum harmala and Desert Truffle (Terfezia spp.): A Novel Integrative Strategy Against Multiple Sclerosis

Background:Multiple sclerosis (MS) is a long-lasting autoimmune condition that affects the central nervous system, characterized by the loss of myelin, neuroinflammation, and immune system imbalances. Although progress has been made in developing disease-modifying therapies, existing treatments often show limited effectiveness and may lead to substantial side effects. Therefore, there is a pressing need for integrative approaches that target neuroimmune mechanisms. Objective:This research focused on investigating the combined neuroimmune-modulating effects of two bioactive-rich natural sources—Peganum harmala and Terfezia spp.—within an AI-informed systems pharmacology framework. Methods:Phytochemicals from both plant sources were identified using established databases and literature reviews. Molecular targets were predicted utilizing SwissTargetPrediction and PharmMapper tools. Compound-target interaction networks were created with STITCH software and visualized through Cytoscape, while protein-protein interactions were assessed via STRING analysis. Pathway enrichment was performed with KEGG and GO-BP methodologies. Molecular docking studies targeted key neuroimmune receptors including TLR4, STAT3, CXCR3, and IL-6R. Synergy modeling was carried out through DeepSynergy and AutoQSAR platforms. ADMET characteristics were estimated using SwissADME and pkCSM tools. Key Results:A total of twenty-one lead compounds were identified; notably, harmine and β-sitosterol showed significant binding affinity for TLR4 and STAT3 receptors. The shared molecular targets were enriched within pathways associated with neuroinflammation and oxidative stress responses. AI analysis revealed three compound pairs exhibiting high synergy scores along with advantageous pharmacokinetic profiles. Conclusion:The combination of these two plants reveals promising in silico synergistic effects on modulating neuroimmune networks pertinent to MS. The outcomes advocate for further preclinical investigations as a potential complementary phytotherapeutic approach.