Targeting systemic lupus erythematosus (SLE) using <i>Withania somnifera</i> derived compounds: A network and molecular dynamics study

BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune disease with a scarcity of effective treatment options and considerable side effects linked to current therapies. <i>Withania somnifera</i>, is rich in phytochemicals that have demonstrated immunomodulatory and anti-inflammatory effects, suggesting its promise as a natural therapeutic candidate for SLE.MethodsAn <i>in silico</i> methodology explored the therapeutic potential of <i>W.</i> <i>somnifera</i> phytocompounds for SLE. Phytochemicals were obtained from Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) and KNApSAcK databases, followed by virtual screening using SwissADME, MOLSOFT, and ProTox 3.0 to identify drug-like and non-toxic candidates. Target genes were predicted using SwissTargetPrediction and STITCH, while SLE-associated genes were compiled from GeneCards and Online Mendelian Inheritance in Man (OMIM). The intersection of these genes was analyzed to construct a protein-protein interaction network, with hub genes identified through Cytoscape. Molecular docking and 100 ns Molecular Dynamic simulations, with Molecular Mechanics, General Born Surface Area (MM-GBSA) free energy calculations, were conducted for lead compounds against top hub proteins.ResultsThe study identified three phytocompounds-vanillic acid, (+)-catechin, and withanolide K-that show favorable pharmacokinetic and toxicity characteristics. Network analysis identified 161 common target genes, with Caspase 3 (CASP3), HIF1A (Hypoxia-inducible factor 1-alpha subunit), Interleukin 1 beta (IL1B), and Interleukin 6 (IL6) as significant hub proteins. Docking studies revealed (+)-catechin and withanolide K have strong binding affinities with IL6 and CASP3. Molecular dynamics simulations confirmed complex stability, and MM-GBSA calculations showed favorable binding free energies, especially in (+)-catechin-protein interactions.Conclusions(+)-Catechin and withanolide K are promising biomolecules for SLE, demonstrating a strong binding affinity with key proteins linked to the disease. These results offer a computational basis for experimental validation and the potential development of safer, plant-based therapies for SLE.