Designing targeted drugs against EGFR protein in the treatment of lung cancer

Abstract

Third-generation covalent EGFR inhibitors, including WZ4002, Osimertinib (AZD9291), and PF-06459988, have been developed to overcome drug resistance by irreversibly binding to specific residues within the EGFR active site, particularly Cys797 and Met790. To investigate these interactions and resistance mechanisms, we performed molecular docking analyses to model and evaluate the binding behavior of these inhibitors with EGFR. Structural results demonstrated that these compounds form highly specific covalent interactions that block EGFR activation and reduce cancer cell signaling. Additionally, second-generation inhibitors such as Afatinib and PD168393 were also shown to covalently bind to Cys797, with 3D structural models highlighting the stable interactions at this critical residue. Comparative docking-based analysis of first-, second-, and third-generation EGFR inhibitors revealed that while early-generation agents like Gefitinib and Afatinib rely on reversible or irreversible binding, newer inhibitors such as WZ4002 and Osimertinib are structurally optimized for enhanced activity against resistant EGFR mutations. The clear distinction between covalent irreversible and covalent-reversible inhibitors further illustrates differences in therapeutic potential. These docking-based findings emphasize the importance of precise molecular design in developing effective treatments against EGFR-driven drug-resistant cancers.