Integrated virtual screening in discovering dual EGFR and Src inhibitor candidates

Src kinase and epidermal growth factor receptor (EGFR) are important mediators of oncogenic signaling pathways involved in cellular survival, proliferation, differentiation, and therapeutic resistance. The activation of EGFR can stimulate Src signaling, which contributes to resistance against EGFR-targeted therapies. Therefore, this study aimed to identify putative dual EGFR and Src-binding candidates using an integrated ligand-based and structure-based computational workflow. Ligand-based pharmacophore models for EGFR and Src were constructed and used to screen purchasable compounds from the ZINC database. The hit compounds obtained from pharmacophore screening were refined through molecular docking using iGEMDOCK 2.1 and AutoDock4.2, with erlotinib as the EGFR inhibitor and dasatinib as the Src inhibitor reference drugs. Six compounds were computationally prioritized as putative dual EGFR and Src binders based on their binding-pose persistence, interaction profiles, and comparative MM/PBSA energetics. Among them, ZINC2770543 demonstrated the most favorable binding profile against both targets. Molecular dynamics simulations revealed that ZINC2770543 maintained stable hydrogen-bond interactions with key residues in EGFR and Src and exhibited favorable binding free energy values compared with the reference inhibitors. The findings indicate that ZINC2770543 may serve as a potential lead compound for further investigation as a putative dual EGFR and Src binder, warranting further experimental validation.