Breast cancer is a complex disease comprising multiple deregulated signaling pathways, oxidative stress, metabolic rewiring, and resistance to therapy. The multi-target therapeutic efficacy of β-sitosterol against breast cancer was studied using an integrated approach that combined network pharmacology, molecular docking, molecular dynamics simulations, and ADMET. Out of which 98 common targets were identified between β-sitosterol and breast cancer, wherein PPARG, TNF, ABL kinase, HIF1A, ESR1, PGR, PPARA, MAPK8, AR, and ESR2 are the key hub genes. The enrichment analysis showed that β-Sitosterol had strong binding affinities towards ABL kinase (-9.7 kcal/mol), PPARA (-9.5 kcal/mol), MAPK8 (-8.7 kcal/mol), and PPARG (-8.6 kcal/mol). Indeed, molecular dynamics simulations were performed for 1000 ns at the molecular level, and the progesterone receptor (PGR) proved to be the most dynamically stable target, as the β-sitosterol-PGR complex remained stable throughout the simulation. The predicted ADMET profile was good. The results suggest that β-sitosterol acts on multiple targets in breast cancer and identify PGR, a target not strongly favored by docking alone, as an important therapeutic target revealed through extended molecular dynamics simulation.
Alma Khan, Srinivas Ganjipete, Prabu Kumar Seetharaman et al.· Computational biology and ch...· 0 citations
Breast cancer is a prevalent and aggressive tumor affecting women, known for its molecular diversity and treatment resistance. This study investigates the anticancer potential of Icariin (ICA), a flavonol glycoside derived from Herba epimedii, against breast cancer using network pharmacology and molecular simulation. Using the SwissTargetPrediction database and GeneCards, the researchers identified 98 common targets shared by ICA and breast cancer. Gene ontology (GO) and KEGG enrichment analyses highlighted the targets' roles in the regulation of apoptosis, inflammatory signaling, receptor tyrosine kinase activity, chemokine signaling, sphingolipid metabolism, and VEGF pathways. Molecular docking revealed ICA's strong binding affinity for key oncogenic proteins, with binding energies ranging from −12 to −7.5 kcal/mol, particularly to SER783, THR862, ASP863, LYS753, and ARG849. Molecular dynamics (MD) simulations demonstrated the structural stability of the ICA‐HER2 complex, which maintained strong hydrogen bonds and exhibited minimal conformational changes over a 1000 ns trajectory, with average RMSD values of 1.7 Å for the protein and 1.0 Å for the protein‐ligand complex. Furthermore, ICA exhibited favorable pharmacokinetic properties, including moderate solubility and negligible inhibition of cytochrome P450. These findings support the hypothesis that ICA may serve as a valuable natural compound for treating HER2‐driven breast cancer; it requires further experimental validation.
