Network pharmacology-based toxicity, molecular docking, and molecular dynamics analysis of phytoconstituents from roots of Nerium indicum L

Abstract

Background

Herbal medicine plays a vital role in healthcare, but safety concerns arise due to potential toxicity risks. Nerium indicum (夹竹桃, jiā zhú táo) is used in Chinese herbal medicine for its therapeutic effects, yet it contains toxic cardiac glycosides. This study investigates its toxicity mechanisms using systems biology tools to support safer applications through comprehensive risk-benefit evaluation and detoxification strategies.

Methods

Computational analyses were performed to predict drug-likeness, toxicity, LD₅₀, and blood-brain barrier (BBB) penetration. Key toxicity-related genes were identified using SwissTargetPrediction and GeneCards. Gene Ontology (GO) and pathway enrichment analyses further explored toxicity mechanisms, while molecular docking and dynamics simulations assessed interactions between core targets, Prostaglandin-endoperoxide synthase 2 (PTGS2) and Mitogen-Activated Protein Kinase 1 (MAPK1), offering deeper insights into toxicity modulation.

Results

Computational analyses identified oleandrin, and odoroside A as highly toxic, with significant cardiotoxic and hepatotoxic risks. Network analysis revealed PTGS2 and MAPK1 as key toxicity regulators, mediating pathways linked to inflammation and cellular stress. Molecular docking showed Oleandrin exhibiting the strongest binding affinities with PTGS2 (-8.5 kcal/mol) and MAPK1 (-9.2 kcal/mol), while molecular dynamics simulations confirmed its stable interactions, suggesting a critical role in toxicity modulation.

Conclusion

This study highlights Oleandrin and related compounds as major toxicity contributors in N. indicum, emphasizing their impact on cardiac, hepatic, and neurological pathways. The findings underscore the need for cautious therapeutic use and potential detoxification strategies for safer applications.