Irilone and Lupinisoflavone C as Potential Plant-Based Modulators of S1PR1 for Neuroimmune Modulation in Multiple Sclerosis: Insights from Molecular Docking and Dynamics.

The S1PR1 gene encodes the sphingosine-1-phosphate receptor 1, a member of the G protein-coupled receptor (GPCR) family that is highly expressed in endothelial cells. S1PR1 protein plays a pivotal role in regulating cell migration, maintaining vascular integrity, and mediating neural signaling through the activation of downstream effectors, including RAC1, SRC, PTK2/FAK1, and MAP kinases. Its critical involvement in neuroinflammation and central nervous system (CNS) homeostasis links S1PR1 to the pathophysiology of neurodegenerative disorders, particularly multiple sclerosis (MS). Overactivation of S1PR1 can trigger chronic inflammation, neuronal injury, and synaptic dysfunction, thereby promoting disease progression. Given its central role in neuroimmune modulation, S1PR1 represents a compelling therapeutic target in MS. This study employed in silico methods to screen phytochemicals from the IMPPAT 2.0 database for their potential as S1PR1 modulators. Compounds were filtered for drug-likeness using physicochemical, ADMET, and PAINS criteria, followed by prediction of biological activity. From this multi-tiered screening, two phytochemicals, Irilone and Lupinisoflavone C, emerged with high binding affinity and favorable interaction profiles toward S1PR1. To further characterize these interactions, all-atom molecular dynamics (MD) simulations, principal component analysis (PCA), and free energy landscape (FEL) mapping were performed. These analyses revealed stable ligand binding that promotes conformational stabilization of S1PR1 upon ligand binding. Taken together, our findings highlight Irilone and Lupinisoflavone C as promising candidates for further in vitro and in vivo investigations aimed at developing anti-MS therapies targeting S1PR1.