Hecogenin derivative as an anti-breast cancer agent: Mechanistic insights from multi-computational analysis

Breast carcinoma poses a significant worldwide health challenge, recording more than 2.3 million incident cases and 665,684 fatalities in 2022, with projections indicating a 38% rise in diagnoses and 68% increase in deaths by 2050, reaching 3.2 million cases and 1.1 million annually, particularly burdening low-income regions. This study investigated the anti-breast cancer potential of the hecogenin derivative CPD1, targeting CDK2 (PDB: 3PXQ), using an integrated computational approach including network pharmacology, molecular docking, dynamics simulations, MMGBSA, ADMET, and DFT analyses. Network analysis revealed 101 shared targets, highlighting several key hubs involved in breast cancer progression. GO enrichments emphasized responses to chemical stimuli and protein kinase activities, while KEGG pathways focused on PI3K-Akt and hormone signaling, revealing CPD1's impact on tumor growth and resistance. Docking suggested a stronger predicted binding tendency of CPD1 (-12.42 kcal/mol) than Ribociclib (-9.73 kcal/mol) under the same computational conditions. Over 100 ns simulations, CPD1-3PXQ displayed greater stability with RMSD around 0.24 nm, aligned RMSF, Rg of approximately 2.0 nm, 1-3 Hbonds, and SASA of about 165 Å². MMGBSA yielded binding energies of -40.47 kcal/mol for CPD1-3PXQ and - 39.04 kcal/mol for Ribociclib-3PXQ, mainly from van der Waals and solvation terms. ADMET confirmed 91.587% intestinal absorption, minimal CYP interference, and no Ames toxicity. DFT and MEP indicated CPD1's broader energy gap (10.7246 eV) and higher hardness (5.3623 eV), suggesting enhanced stability and reactivity balance. These insights position CPD1 as a viable CDK2 inhibitor for breast cancer, underscoring the need for in vitro and in vivo confirmation to refine its clinical promise.