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Integrated Network Pharmacology and Molecular Dynamics Reveal Luteolin from Persea americana as a Multi-Cancer
Akey Krishna Swaroop1, Bharat Kumar Reddy Sanapalli2, Jubie Selvaraj3
1Department of Pharmaceutical Chemistry, Shri Vile Parle Kelavani Mandal's College of Pharmacy, Shirpur 425421, MH, India.
Abstract:
Cancer progression is driven by dysregulated kinase signaling and apoptotic evasion across multiple malignancies. Although targeted kinase inhibitors have improved outcomes, resistance and toxicity remain major challenges. Natural phytochemicals offer promising multi-target therapeutic potential. Persea americana contains diverse bioactive compounds; however, its role in multi-cancer kinase targeting remains underexplored. This study aimed to identify and validate anti-cancer kinase targets of Persea americana phytoconstituents across five cancers: lung, breast, cervical, colorectal, and prostate, using integrated network pharmacology and molecular simulation approaches. Cancer-associated genes were retrieved from the Open Targets Platform and prioritized through Gene Ontology analysis. Overlapping targets with 208 predicted human targets of Persea americana were identified. Protein-protein interaction networks revealed hub genes, followed by TCGA-based validation. Twenty-five phytoconstituents were docked against SRC and GSK3β, and top complexes underwent 100 ns molecular dynamics simulations. Enrichment highlighted kinase activity and apoptosis. SRC emerged as a pan-cancer hub, while GSK3β was prominent in breast cancer. Luteolin showed strongest binding to SRC (-11.9 kcal/mol), outperforming the co-crystal inhibitor, while valencene showed affinity toward GSK3β (-8.8 kcal/mol). Simulations confirmed stable interactions. Luteolin exhibits strong multi-target kinase inhibition, particularly against SRC, supporting its potential as a pan-cancer therapeutic candidate.
Insights
Persea americana compounds, like luteolin, show potential for multi-cancer treatment by targeting key kinases such as SRC. This research identifies natural compounds as promising therapeutic candidates for various cancers.
Area of Science:
- Pharmacology
- Computational Biology
- Oncology
Background:
- Cancer progression involves dysregulated kinase signaling and evasion of apoptosis.
- Targeted kinase inhibitors face challenges of resistance and toxicity.
- Natural phytochemicals, like those in Persea americana, offer multi-target therapeutic potential but remain underexplored for kinase targeting.
Purpose of the Study:
- To identify and validate anti-cancer kinase targets of Persea americana phytoconstituents.
- To investigate the potential of Persea americana compounds against lung, breast, cervical, colorectal, and prostate cancers.
- To integrate network pharmacology and molecular simulations for target identification.
Main Methods:
- Retrieved cancer-associated genes from Open Targets Platform and prioritized using Gene Ontology analysis.
- Identified overlapping targets between cancer genes and predicted Persea americana targets.
- Utilized protein-protein interaction networks, TCGA data, molecular docking, and molecular dynamics simulations.
Main Results:
- SRC was identified as a pan-cancer hub kinase, while GSK3β was prominent in breast cancer.
- Luteolin demonstrated strong binding affinity to SRC (-11.9 kcal/mol), surpassing the co-crystal inhibitor.
- Valencene showed affinity for GSK3β (-8.8 kcal/mol), with simulations confirming stable interactions.
Conclusions:
- Luteolin exhibits potent multi-target kinase inhibition, particularly against SRC, highlighting its potential as a pan-cancer therapeutic agent.
- Persea americana phytoconstituents show promise for developing novel anti-cancer therapies.
- Integrated network pharmacology and molecular simulations are effective for identifying natural product-based therapeutic targets.
