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Integrated docking-molecular dynamics, ADME-toxicity profiling, and transcriptomic validation identify oroxylin a as
Nourah Albarrak1, Hanadi Albjeedi1, Ebtihal Kamal2
1Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.
Background:
Systemic lupus erythematosus (SLE) remains difficult to control despite current therapies, highlighting the need for more selective, mechanism-based treatments targeting key innate immune components such as Toll-like receptor 7 (TLR7).
Objectives:
To identify natural flavonoid compounds with favorable stability and drug-like properties as hypothesis-generating TLR7 inhibitors for SLE using an integrated in silico workflow.
Methods:
Six flavonoids (bavachinin, baicalein, apigenin, wogonin, eupalitin, and oroxylin A) were screened against TLR7 using molecular docking and 100-ns molecular dynamics simulations of the two top-scoring complexes. Drug likeness and ADME-toxicity were assessed using in silico toxicity models. KEGG pathway enrichment of predicted flavonoid targets was performed, and two independent SLE GEO datasets (GSE65391 and GSE61635) were analyzed to define upregulated genes and identify overlap with predicted targets retrieved from SwissTargetPrediction.
Results:
Docking identified bavachinin and oroxylin A as the strongest initial binders to TLR7, while molecular dynamics showed that the oroxylin A-TLR7 complex exhibited greater conformational stability and more persistent interactions than bavachinin. Both ligands met drug-likeness criteria, but oroxylin A displayed a more balanced ADME-toxicity profile and less toxicity than the more lipophilic, immunotoxic bavachinin. KEGG enrichment of predicted oroxylin A targets highlighted inflammatory and immune-related pathways, and 12 predicted oroxylin A targets were consistently upregulated across both SLE datasets.
Conclusion:
Oroxylin A showed the most favorable combination of TLR7 complex stability, ADME-toxicity properties, immune-related pathway enrichment, and overlap with SLE-upregulated genes, supporting its prioritization as a potential TLR7-directed, hypothesis-generating candidate for SLE that warrants rigorous in vitro and in vivo validation.