Integrative Network Pharmacology and Molecular Docking Reveal the Multitarget Anti-HGSOC Potential of Pterocarpus marsupium Phytoconstituents via Modulation of HIF-1α-Driven Inflammation-Metabolism Crosstalk

Background

High-Grade Serous Ovarian Cancer (HGSOC) is the most lethal gynaecological malignancy, and its progression is driven substantially by Hypoxia-Inducible Factor-1α (HIF-1α)-centred inflammation-metabolism crosstalk that underlies chemoresistance. Pterocarpus marsupium, a plant used in Ayurvedic medicine for inflammatory and metabolic disorders, has not previously been investigated against HGSOC.

Purpose

This study aimed to identify bioactive P. marsupium phytochemicals capable of multitarget modulation of the HIF-1α-driven hypoxia-inflammation-metabolism axis in HGSOC, using an integrated network pharmacology and molecular docking approach.

Materials and Methods

Phytochemicals curated from the IMPPAT database were filtered using Lipinski's Rule of Five, SwissADME-predicted pharmacokinetics, and ProTox-3.0 toxicity screening. Putative human targets, predicted with SwissTargetPrediction, were intersected with HGSOC-associated genes from GeneCards and OMIM. A protein-protein interaction network was built in STRING/Cytoscape, and hub genes and functional modules were identified using cytoHubba and MCODE. Gene Ontology and KEGG pathway enrichment were performed in DAVID. Twenty-one drug-like phytochemicals were docked in triplicate, using CB-Dock, against five network-prioritised targets central to the hypoxia-glycolysis-survival axis - Factor Inhibiting HIF-1 (FIH-1/HIF1AN, a direct upstream regulator of HIF-1α transactivation), PDK1, LDHA, MTOR, and STAT3 - and redocking of native co-crystallised ligands with RMSD analysis was performed to benchmark pose reliability.

Results

Network analysis identified 107 shared targets and highlighted HIF1A, IL6, EGFR, ESR1, and BCL2 as central regulatory hubs enriched in HIF-1, PI3K-Akt, and ErbB signalling pathways. Molecular docking showed that Pseudobaptigenin, 3,7,4′-trihydroxyflavone, and marsupsin achieved binding affinities of -8.3 to -9.7 kcal/mol across the panel, and redocking of native ligands reproduced experimental poses with RMSD values mostly below 2.0 Å, supporting the reliability of the docking protocol.

Conclusion

These findings, supported by redocking/RMSD-validated binding poses, suggest that P. marsupium phytochemicals may act as multitarget modulators of the HGSOC hypoxia-inflammation-metabolism axis, offering a testable molecular rationale that bridges traditional Ayurvedic use with systems pharmacology. As this is an entirely computational study, these results are hypothesis-generating rather than confirmatory, and experimental validation is required before any therapeutic potential can be inferred.