Overexpression of BRF2, the essential subunit of RNA polymerase III, is required for the development of a variety of cancers, including lung squamous cell carcinoma and breast cancer. BRF2 also acts as a central redox-sensing transcription factor (TF) and is involved in the regulation of oxidative stress (OS) pathway where its amplification enables cancer cells to evade OS-induced apoptosis. Here, we experimentally confirmed a link between BRF2 and DNA damage response (DDR) signaling. Focusing on its DNA binding capacity, we targeted BRF2-TATA binding Protein (TBP)-DNA complex interaction to functionally inhibit this transcription factor (TF). We found that BRF2 binding to TBP changes the conformation of this protein and therefore characterized these events in detail. Virtual screening allowed selection of the optimal drug based on binding energy, and intermolecular, internal, and torsional energy parameters. Molecular dynamics simulation confirmed the docking results and all simulations were validated by root‐mean‐square deviation (RMSD). According to the simulation, the chosen drug was efficacious in targeting BRF2 which therefore requires further experimental validation to investigate the effect of this drug on BRF2 functions and its downstream pathways.