Protopine as a Potential Breast Cancer Therapeutic: A Computational Study Targeting PIK3CA and Cancer Networks

Abstract Breast cancer is driven by complex oncogenic mechanisms, including aberrant signaling pathways and genetic mutations. Current therapies often face limitations, such as drug resistance and adverse effects, necessitating the identification of novel therapeutic agents. Protopine, known for its anticancer properties in other malignancies, remains unexplored for breast cancer. This study investigates the therapeutic potential of protopine in breast cancer by examining its effects on critical molecular targets and signaling pathways involved in tumor progression and metastasis through computational pharmacological approaches. Breast cancer‐associated targets were identified, and protopine's binding affinity for PIK3CA was evaluated using molecular docking and molecular dynamics simulations. Binding stability and dynamics were assessed using RMSD, hydrogen bonding analysis, and MM‐PBSA energy calculations. Protopine exhibited multitargeted activity, interacting with 17 breast cancer‐associated targets, including PIK3CA, CHEK1, and CDK2. It modulated critical pathways such as PI3K‐Akt, JAK‐STAT, and VEGF, disrupting processes like cell proliferation and angiogenesis. Molecular docking showed strong binding affinity for PIK3CA (−9.2 kcal/mol), while molecular dynamics confirmed stable binding with favorable free energy (−6.71 ± 0.64 kcal/mol). Protopine demonstrated significant therapeutic promise as a multitargeted agent, modulating key oncogenic pathways and providing the potential to overcome resistance and improve breast cancer therapies.