Repurposing Antiviral Drugs as Potential Anti‐EGFR Agents in NSCLC: A Structure‐Based Screening and Molecular Dynamics Analysis

Abstract

Abstract One of the problems resulting from recurrent hyperactivated or mutant epidermal growth factor receptors (EGFR) in non‐small cell lung cancer (NSCLC) is therapeutic resistance. Consequently, this leads to increased expression of oncogenic proteins and reduces the efficacy of EGFR tyrosine kinase inhibitors (TKIs). This study assessed antiviral drug efficacy as potential anti‐EGFR agents for NSCLC. We used structure‐based virtual screening to evaluate 66 antiviral drugs thoroughly. The top 6 antiviral drugs exhibiting impressive binding energies (i. e. surpassing a threshold of −8.5 kcal mol −1 ) were identified. Subsequent bioactivity analysis and ADMET profiling were performed to select the most promising candidates, followed by a molecular dynamic simulation. Among the selected antiviral regimens, dolutegravir demonstrated the highest docking score (−9.8 kcal mol −1 ), followed by rilpivirine and ensitrelvir, surpassing other candidates and our reference EGFR TKI. Further molecular dynamics simulations revealed promising dynamic interactions of dolutegravir, ensitrelvir, and rilpivirine with the EGFR target as compared with afatinib. Our findings highlight the repositioning potential of antiviral drugs for anti‐EGFR drug discovery, supported by their robust docking scores, ADMET profiles, dynamic interactions, and binding free energies. The results open up new avenues for advanced NSCLC therapy. Further in vitro investigations are warranted to evaluate their efficacy and safety.