Integrated network pharmacology and molecular docking analysis to elucidate the mechanism of action of two bioactive diterpenoid lactones isolated from Andrographis paniculata in wound repair process

Abstract

Background

Chronic and acute wounds remain a worldwide health challenge, predominantly in patients with diabetes, aging populations, and trauma-related injuries, necessitating safe, multi-targeted wound-healing agents. Andrographis paniculata, a medicinal plant with diverse phytochemicals mainly diterpenoids with significant medicinal value. This investigation explored their molecular mechanisms in wound repair through integrated network pharmacology and molecular docking.

Methodology

Hydroalcoholic extracts of A. paniculata were purified chromatographically to yield two major metabolites, AP-1 and AP-2, characterized by NMR and HR-ESI-MS. Their antibacterial activity was evaluated using MIC assays, while antioxidant potential was assessed through DPPH, hydroxyl radical, and nitric oxide scavenging assays. Drug-likeness and ADMET properties were evaluated in silico. Putative targets were predicted using SwissTargetPrediction, Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and complementary databases, while wound-healing and inflammation-associated genes were retrieved from GeneCards and DisGeNET. Protein–protein interaction (PPI) networks, hub gene identification, and pathway enrichment were analyzed using STRING, Cytoscape, GO, and KEGG. Molecular docking was executed with AutoDock Vina to assess ligand–protein interactions.

Results

Isolated AP-1 and AP-2 were identified as andrographolide and 14-deoxy-11,12-didehydroandrographolide, respectively. These compounds exhibited good antibacterial and anti-oxidant activity. AP-1 & AP-2 exhibited favourable ADMET profiles with oral bioavailability >30% and drug-likeness scores >0.18. Network pharmacology identified 315 compound-related targets, with 12 common overlapping genes central to inflammation, antioxidant response, antimicrobial defense, and wound healing (e.g., AKT1, IL6, IL1β, TNF, NF-κB1). Hub gene analysis highlighted TNF, IL6, EGFR, and AKT1. GO/KEGG enrichment revealed regulation of IL-17, TNF, and AGE-RAGE signaling pathways, relevant especially to diabetic wound complications. Docking confirmed strong binding affinities, with AP-2 showing superior interactions, particularly with AKT1 (−9.4 kcal/mol), IL-10 (−8.3 kcal/mol), and TNF (−8.2 kcal/mol).

Conclusion

This integrative analysis demonstrates that A. paniculata diterpenoid lactones, especially AP-2, exert multi-target modulatory effects on key wound-healing pathways. Their favorable pharmacokinetic profiles and siginifcant binding affinities support their potential as lead phytotherapeutics for wound management, warranting further experimental validation.