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

Abstract

Background

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a scarcity of effective treatment options and considerable side effects linked to current therapies. Withania somnifera, is rich in phytochemicals that have demonstrated immunomodulatory and anti-inflammatory effects, suggesting its promise as a natural therapeutic candidate for SLE.

Methods

An in silico methodology explored the therapeutic potential of W. somnifera 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.

Results

The 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.