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Purpose <p><i>Wendlandia heynei</i>(Rubiaceae) is traditionally used for treating various ailments, yet its comprehensive pharmacological potential remains underexplored. This study aimed to characterize the plant metabolome, identify key bioactive compounds, and elucidate the molecular mechanisms underlying its cytotoxic and other biological activities.</p> Methods <p>High-resolution liquid chromatography–mass spectrometry (HR-LCMS) profiling of the hydroalcoholic leaf extract was performed to identify phytocompounds. In-vitro assays evaluated cytotoxic, antioxidant, anti-inflammatory, and enzyme inhibitory activities. Network pharmacology was employed to predict compound–target–pathway interactions related to breast cancer. Molecular docking and 100 ns molecular dynamics (MD) simulations (Schrödinger Desmond) were used to assess binding affinity and stability of protein–ligand complexes.</p> Results <p>HR-LCMS analysis identified 91 phytocompounds, predominantly belonging to flavonoids and phenolic acids, among which kaempferol, genistein, gallic acid, syringic acid, vanillic acid, benzoic acid, 6-hydroxymelatonin and 8S-HODE were identified as major key metabolites and prioritized based on drug-likeness and target relevance. The extract exhibited significant cytotoxic activity against MCF-7 breast cancer cells (IC₅₀ = 56.63 ± 2.7 µg/mL), along with notable antioxidant, anti-inflammatory, and enzyme inhibitory activities against α-amylase, α-glucosidase, urease, and pancreatic lipase. Network pharmacology analysis revealed 105 human target genes and 103 breast cancer associated overlapping targets with enrichment of key cancer-related pathways, particularly PI3K-Akt and MAPK signaling pathways. Protein–protein interaction analysis identified ESR1, EGFR, MMP9, GSK3B, and PPARA as key hub genes. Molecular docking demonstrated strong binding affinities of genistein and kaempferol with these targets. MD simulations confirmed the stable ESR1-genistein complexs, characterized by persistent interactions with GLU353, LEU387, ARG394, PHE404, GLU419, GLY420, and TYR526, whereas Doxorubicin and Tamoxifen displayed higher flexibility. Also, stable interactions with MMP9 (key residues such as HIS401, GLU402, PHE425, ARG424, and THR426 interacted with genistein) Collectively, the results highlight genistein and kaempferol as major contributors to the anticancer effects of <i>W. heynei</i> through a synergistic multi-compound, multi-target, and multi-pathway mechanism.</p> Conclusion <p>The current research highlights the comprehensive exploration of <i>W. heynei</i> for various treatments like, cancer, inflammation, diabetes, obesity and microbial associated ulcers. The study signifies and establishes an integrated analytical framework combining HR-LCMS profiling, network pharmacology, molecular docking and dynamics simulations to evaluate the pharmacological potential of <i>W. heynei</i> by correlating its metabolite diversity with breast cancer molecular targets and pathways to deliver mechanistic insights and scientific validations to the traditional medicinal use thereby identifying bioactive leads for future drug development.</p> Graphical Abstract <p></p>

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Bioactive HR-LCMS Analyzed Phytocompounds from Wendlandia heynei (Rubiaceae) Explored for PI3K-Akt and MAPK Pathways Mediated Tumor Suppression and Biological Attributes through In-vitro and Integrated Network Pharmacology, Docking and Simulations

  • 期刊论文

  • 发表日期：

    2026年4月22日

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  • Zabin K. Bagewadi,
  • Chinmay G. Hiremath,
  • Nayef Abdulaziz Aldabaan,
  • Pratiksha B. Kumbar,
  • Adel M. Aljadaan,
  • Shivanand S. Bhat,
  • Vishal S. Patil,
  • Ibrahim Aljaezi,
  • Ibrahim Ahmed Shaikh,
  • Basheerahmed Abdulaziz Mannasaheb

摘要

Purpose

Wendlandia heynei(Rubiaceae) is traditionally used for treating various ailments, yet its comprehensive pharmacological potential remains underexplored. This study aimed to characterize the plant metabolome, identify key bioactive compounds, and elucidate the molecular mechanisms underlying its cytotoxic and other biological activities.

Methods

High-resolution liquid chromatography–mass spectrometry (HR-LCMS) profiling of the hydroalcoholic leaf extract was performed to identify phytocompounds. In-vitro assays evaluated cytotoxic, antioxidant, anti-inflammatory, and enzyme inhibitory activities. Network pharmacology was employed to predict compound–target–pathway interactions related to breast cancer. Molecular docking and 100 ns molecular dynamics (MD) simulations (Schrödinger Desmond) were used to assess binding affinity and stability of protein–ligand complexes.

Results

HR-LCMS analysis identified 91 phytocompounds, predominantly belonging to flavonoids and phenolic acids, among which kaempferol, genistein, gallic acid, syringic acid, vanillic acid, benzoic acid, 6-hydroxymelatonin and 8S-HODE were identified as major key metabolites and prioritized based on drug-likeness and target relevance. The extract exhibited significant cytotoxic activity against MCF-7 breast cancer cells (IC₅₀ = 56.63 ± 2.7 µg/mL), along with notable antioxidant, anti-inflammatory, and enzyme inhibitory activities against α-amylase, α-glucosidase, urease, and pancreatic lipase. Network pharmacology analysis revealed 105 human target genes and 103 breast cancer associated overlapping targets with enrichment of key cancer-related pathways, particularly PI3K-Akt and MAPK signaling pathways. Protein–protein interaction analysis identified ESR1, EGFR, MMP9, GSK3B, and PPARA as key hub genes. Molecular docking demonstrated strong binding affinities of genistein and kaempferol with these targets. MD simulations confirmed the stable ESR1-genistein complexs, characterized by persistent interactions with GLU353, LEU387, ARG394, PHE404, GLU419, GLY420, and TYR526, whereas Doxorubicin and Tamoxifen displayed higher flexibility. Also, stable interactions with MMP9 (key residues such as HIS401, GLU402, PHE425, ARG424, and THR426 interacted with genistein) Collectively, the results highlight genistein and kaempferol as major contributors to the anticancer effects of W. heynei through a synergistic multi-compound, multi-target, and multi-pathway mechanism.

Conclusion

The current research highlights the comprehensive exploration of W. heynei for various treatments like, cancer, inflammation, diabetes, obesity and microbial associated ulcers. The study signifies and establishes an integrated analytical framework combining HR-LCMS profiling, network pharmacology, molecular docking and dynamics simulations to evaluate the pharmacological potential of W. heynei by correlating its metabolite diversity with breast cancer molecular targets and pathways to deliver mechanistic insights and scientific validations to the traditional medicinal use thereby identifying bioactive leads for future drug development.

Graphical Abstract