Discovery of Novel Dual EGFR/HER2 Inhibitors Using Integrated Docking, Molecular Dynamics, and MMGBSA Computational Approaches

Abstract  Epidermal growth factor receptor (EGFR) and HER2 are key drivers of tumorigenesis in many cancers, but resistance to targeted therapies often arises through compensatory signaling. To address this, we employed an integrated in silico protocol using Maestro (Schrödinger) to identify potential dual EGFR/HER2 inhibitors. Ligands were first filtered for drug‐likeness using QikProp. Crystal structures of EGFR (PDB: 3W32) and HER2 (PDB: 3PP0) were prepared, and docking grids were centered on the ATP‐binding pocket. SP and XP docking of four novel ligands (L1–L4) and known inhibitors was performed, followed by 100‐ns MD simulations and MMGBSA free energy calculations. The novel ligands exhibited favorable ADMET profiles and strong binding affinities (−12 to −14 kcal/mol), comparable to or better than known inhibitors. MD and MMGBSA confirmed complex stability and strong energetics. This approach identified promising dual inhibitors, supporting further experimental validation for cancer therapy development.