Targeting EGFR in cancer using Terminalia arjuna: An integrated In Silico, molecular dynamics, experimental...

The Epidermal Growth Factor Receptor (EGFR) plays a pivotal role in 20-60% of cancer cases, including glioblastoma, lung adenocarcinoma, and head and neck squamous cell carcinoma, as reported in The Cancer Genome Atlas (TCGA) dataset. The present study employed an integrated in silico and experimental workflow to evaluate EGFR-targeted compounds from Terminalia arjuna. Drug-likeness and ADMET screening were performed, followed by molecular docking and 1000 ns molecular dynamics simulations. In vitro validation was conducted using cancer cell-based assays and network pharmacology to explore the molecular mechanisms associated with the identified compound. Screening shortlisted eight compounds from T. arjuna. Molecular docking identified Arjunaside C (-8.2 kcal/mol), Arjunapthanoloside (-7.7 kcal/mol), and Beta-sitosterol (-7.4 kcal/mol) as potential EGFR inhibitors compared to Erlotinib (-6.6 kcal/mol). Arjunapthanoloside formed more H-bonds and exhibited most stable interactions with EGFR. MD simulations at 1000 ns revealed lower RMSD, RMSF, SASA, and Rg values for the Arjunapthanoloside-EGFR complex, indicating enhanced stability. Direct binding validation was limited by the unavailability of purified Arjunapthanoloside; therefore, Arjuna extract was evaluated, which demonstrated potent cytotoxicity with an IC₅₀ of 9 µg/mL in H357 oral cancer cells. Flow cytometry confirmed apoptosis-mediated cell death by increased early- and late-apoptotic cell populations. Network pharmacology analysis further identified additional targets (MMP3, MMP7, MMP9, and HRAS) that are directly involved in various cancers. Overall, the findings provide new insights into the therapeutic potential of Arjunapthanoloside as a stable compound that interacts with EGFR from T. arjuna, highlighting its significance in EGFR-targeted anticancer research.