In Silico Study of Bis(6‐Amino‐1,3‐Dimethylpyrimidine‐2,4(1H,3H)‐Diones) as EGFR Inhibitors: Synthesis, DFT, Molecular Docking, and MD Simulation Studies

The epidermal growth factor receptor (EGFR), a protein located on the cell surface, belongs to the tyrosine kinase family and plays a crucial role in cell development and proliferation. Abnormal expression or mutations in the EGFR gene can lead to non–small cell lung cancer. Although established EGFR inhibitors have been effective in the treatment of cancer, they are associated with several side effects. As a result, there is an urgent need to develop novel EGFR inhibitors that can effectively target the receptor while causing no adverse side effects. In this study, a series of bis(6‐amino‐1,3‐dimethylpyrimidine‐2,4(1 H ,3 H )‐dione derivatives was synthesized in water at room temperature without the use of any catalyst, and pharmaceutical properties are investigated. Computational methods, including density functional theory (DFT), molecular docking, and molecular dynamics (MD), were utilized to investigate the chemical properties, drug‐like characteristics, and anticancer potential of the molecule. Quantum chemical calculations indicated that the molecules are relatively stable and exhibit significant electrophilic properties. The analysis of HOMO‐LUMO contour maps was conducted to illustrate charge density distributions that may be associated with biological activity. Docking studies with EGFR enzymes indicated that all compounds demonstrated favorable binding affinities, with docking scores ranging from −4.412 to −6.158 kcal/mol. Particularly, Compound 3f, with an energy of −6.158 kcal/mol, showed the best binding affinity, outperforming the native ligand, which had a docking score of −5.076 kcal/mol. The stability of the EGFR‐3f complex is significantly enhanced by the formation of five conventional hydrogen bonds and one carbon–hydrogen bond in ligand–protein interactions. MD simulations, which included analyses such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (rGyr), molecular surface area (MolSA), and polar surface area (PSA), were conducted on the EGFR‐3f complex. It was found that the EGFR‐3f complex is stable, and the results show that Compound 3f has a strong interaction with the target enzyme.