From virtual screening to cell-based assays: structure-guided identification of EGFR-targeting perimidine derivatives with anticancer activity.

Breast cancer remains a significant health issue based on its increasing incidence, multidrug resistance, and associated increased mortality rate. The overexpression of epidermal growth factor receptor (EGFR) has been significantly correlated with the pathogenesis and aggressiveness of various subtypes of breast cancer. In this study, we explored a series of perimidine-derived small molecules as potential EGFR-targeting candidates using a structure-guided approach. A virtual library of 201 derivatives of perimidine was built and screened by molecular docking against four EGFR isoforms (PDB IDs: 4HJO, 1M17, 4I23, and 5UGB) with the Schrödinger Suite. Out of these, two lead candidates, Compound 101 and Compound 201, exhibited better binding affinity and good interaction profiles. Molecular dynamics (MD) simulations were also carried out to determine the conformational stability of the lead compounds at the EGFR binding site, compared with their respective co-crystallized standards. Compound 201 consistently ranked among the top predicted binders across all four target structures (4HJO, 1M17, 4I23, 5UGB), and cross-target rank correlation analysis supported target-consistent binding behavior for selected compounds. ADMET profiling by Swiss ADME and ADMETlab 3.0 indicated good pharmacokinetic and toxicity parameters evidencing their drug-likeness along with some pharmacokinetic parameters which warrant further optimization. The chosen compounds were synthesized and structurally elucidated, and theoretical validation was established by DFT analysis. Following in vitro cytotoxicity evaluation by MTT assay on MCF-7 breast cancer cells along with an EGFR-relevant triple-negative breast cancer (TNBC) cell line, differential and considerable cytotoxicity was found. Overall, these results indicate that perimidine-based molecules, particularly Compound 101 and Compound 201, are promising compounds towards the development as EGFR-targeting anticancer drugs; however, further biochemical and cellular target-validation studies are required to confirm direct EGFR inhibition and their therapeutic potential.