Unveiling the mechanism of action of Cymarin in combating breast cancer: An integrated computational analysis.

Breast cancer remains a critical worldwide health issue, accounting for approximately 2.3 million new diagnoses and 665,684 deaths in 2022, underscoring the urgent need for novel interventions. This investigation examined Cymarin's potential as an anti-breast cancer compound, focusing on MAPK8 (4L7F), through integrated network pharmacology, molecular docking, dynamics simulations, MMGBSA, ADMET, and DFT evaluations. Network analysis pinpointed 95 shared targets, constructing a PPI network with 30 nodes and 219 edges, emphasizing hub genes such as STAT3, JUN, BCL2L1, MAPK8, and MAPK1. GO enrichment highlighted signaling regulation and kinase activities, while KEGG pathways implicated oncogenic cascades, AGE-RAGE signaling, TRP-mediated inflammation, apoptosis, and insulin resistance. Docking revealed Cymarin's favorable binding affinity (-9.69 kcal/mol) compared to Tamoxifen (-9.31 kcal/mol), driven by hydrogen bonds, van der Waals, and hydrophobic contacts. A 200 ns molecular dynamics simulation suggested that the Cymarin-MAPK8 complex maintained a generally more stable dynamic profile than Tamoxifen-MAPK8. MMGBSA confirmed superior binding free energy for Cymarin (-34.58 kcal/mol) compared to Tamoxifen (-25.87 kcal/mol), primarily from van der Waals and electrostatic contributions. ADMET profiling indicated Cymarin's favorable absorption (73.688%), absence of CYP inhibition, and non-mutagenic profile. DFT metrics suggested Cymarin's enhanced stability with a slightly wider energy gap (10.5787 eV) and higher hardness (5.2894 eV). These findings position Cymarin as a compelling multi-target candidate, warranting empirical confirmation.