Repurposing Pyrrolopyrimidine Schiff Base Transition Metal(II) Complexes for Anticancer Activity: Computational Insights into EGFR Inhibition

Pyrrolopyrimidine scaffolds are well-recognized in the development of EGFR inhibitors and remain a privileged framework for anticancer drug discovery. Transition metal (II) complexes with tridentate Schiff bases derived from pyrrolopyrimidines have previously been explored for their antimalarial and antioxidant properties. However, their potential as anticancer agents, particularly EGFR inhibitors, has not been investigated. Based on this rationale, it is hypothesized that such complexes may also exhibit inhibitory activity against EGFR, and applied a computational repurposing strategy to assess their potential. Among the screened complexes, Compound 3 displayed favorable docking within the ATP-binding cleft of EGFR, establishing interactions with hinge and catalytic residues such as Phe723 and Cys797. To validate its stability under physiological conditions, a 200 ns molecular dynamics simulation was conducted, followed by analyses of RMSD, RMSF, ligand–protein contacts, PCA, FEL, and MM/GBSA calculations. The EGFR–Compound 3 complex showed a slight reduction in flexibility within certain functional regions compared with the apo form, suggesting a tendency toward local stabilization. This study provides the first evidence that pyrrolopyrimidine-based transition metal (II) complexes may act as potential EGFR inhibitors, highlighting their potential based on preliminary computational evidence and supporting further experimental validation