NRTK Cytoplasmic Odyssey: Modeling Natural Products as Dual Abl and Src Antagonists in Breast Cancer Enigma

Breast cancer remains a complex disease characterized by dysregulation of multiple oncogenic signaling pathways, with Abl and Src kinases playing pivotal roles in tumor progression, metastasis, and therapy resistance. Targeting these kinases simultaneously presents an attractive therapeutic strategy but is complicated by the structural diversity and dynamic behavior of kinase active sites. In this study, we established a multi-layered cheminformatics workflow to identify natural products with dual Abl/Src antagonistic potential. An initial virtual screening campaign employing Glide XP docking and Prime MM/GBSA rescoring was conducted against crystallographic Abl and Src structures, followed by redocking validation (RMSD ≤ 0.15 Å) to ensure protocol reliability. Density functional theory (DFT) optimizations refined ligand geometries and electronic properties, producing energetically favorable conformations for subsequent evaluations. Molecular dynamics (MD) simulations of 500 ns for top ligand-protein complexes were analyzed using RMSD, RMSF, radius of gyration, SASA, and hydrogen-bond profiling to assess stability and conformational flexibility. Free energy landscape (FEL) analysis revealed well-defined energetic basins corresponding to stable ligand binding. Post-MD MM/GBSA calculations confirmed favorable binding free energies, while quantum descriptors from DFT, including HOMO-LUMO gaps and electrostatic potentials, corroborated electronic stability. Collectively, Hesperidin, Rhapontin, and Maillard emerged as lead natural products, demonstrating superior thermodynamic and electronic profiles compared to the reference inhibitor Inavolisib. Beyond identifying specific candidates, this study introduces a reproducible and transferable cheminformatics framework that integrates docking, dynamics, and quantum-level analysis, providing a generalizable strategy for rational kinase inhibitor discovery across cancer and other disease contexts.