Mechanistic Insights of Corylifol A-Mediated EGFR Inhibition and Network Modulation in Breast Cancer: A Computational Pharmacology Study

Background: Uncontrolled proliferation and resistance to treatments are caused by abnormal activation of oncogenic signaling networks, such as the epidermal growth factor receptor (EGFR) axis. Multitarget potentials of natural compounds, which can be used as an alternative to counteract such limitations, have a promising future. This study examines the molecular pathway and therapeutic efficacy of Corylifol A in the modulation of EGFR-breast cancer by a combined computational pharmacology strategy. Materials and Methods: Possible Corylifol A targets were also determined by chemogenomic databases and overlapped with genes associated with breast cancer. Functional pathways were analyzed by network pharmacology, Gene Ontology, and KEGG enrichment, and the network was constructed using Cytoscape 3.10.0. The binding affinity and stability were assessed using Schrodinger Suite to calculate molecular docking, MM-GBSA, and 100-ns molecular dynamics (MD) simulations. Further, the ADMET properties were assessed using AdmetSAR 3.0. Results: EGFR was found to be the core node of the network of the Corylifol A-pathways. Corylifol A exhibited high binding affinity (-5.48 kcal/mol and ΔG bind -128.62 kcal/mol) through hydrogen bonding with Met 769 with EGFR, holding the receptor in the inactive form and possibly modulating PI3K-Akt, JAK-STAT, and ER crosstalk pathways. Complex stability was validated by MD simulations, and favorable absorption and low toxicity were predicted by ADMET results. Conclusion: Corylifol A exhibited strong EGFR-targeting and multitarget modulatory activity against BC. Its interactions with the network also indicated a regulation of compensatory oncogenic pathways, which should be further validated by in vitro and in vivo experiments.