Molecular docking has become a significant approach in drug discovery and nanotoxicology, as it enables large-scale genomic, proteomic, and nanomaterial data studies, through virtual screening, lead optimization, and side-effect prediction. This chapter outlines the fundamental aspects and significant applications of molecular docking simulation, emphasizing nano-biointeractions and potential side-effect/nanotoxicity relationship prediction. It discusses the expert curation and state-of-the-art structure-based methods to systemically address these challenges, focusing on key nanoparticle interactions at the molecular level, particularly regarding DNA interaction, towards a rational nanomaterial design with the desired lowest nanotoxicity possible for safer biomedical applications. Finally, the gaps and challenges of the field are identified and integrated solutions are proposed.