Discussion Oxidative stress results when the antioxidant response is not sufficient to balance the production of reactive oxygen species (ROS). Fortunately, the cell contains antioxidant defence pathways that are essential for cell survival. However, dysfunction and up regulation of the oxidative stress pathways have been implicated in the pathogenesis of many neurodegenerative diseases, including, for example, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein is an important transcription factor that ordinarily is sequestered in an inactive form within the cytoplasm by association the Kelch-like erythroid cell-derived protein with CNC homology-associated protein (Keap1) protein. However, when it senses oxidative stress, Nrf2 dissociates from Keap1 and translocates to the nucleus to activate the transcription of antioxidant enzymes such as, the phase II detoxifying enzymes glutathione S-transferase (GST), quinone reductase (QR), heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Modulation of the Nrf2 pathway is therefore an attractive cellular pathway for drug discovery. In order to identify a novel Nrf2 activator that disrupts the Nrf2-Keap1 protein-protein interaction, we performed a virtual screen bases upon the known structure of the protein interface and evaluated compounds in a DiscoveRx nuclear complementation assay that measures the translocation of Nrf2 from the cytoplasm to the nucleus. In this assay, sulforaphane was used as a positive control and had an EC50 of 400 ± 55 nM. Of the 122 virtual screening “hits” that were evaluated, five produced an activation of 15%, 20%, 25%, 40% and 100% respectively (percentage normalised using sulforaphane control). However, the use of a ROS-Glo assay showed that three of these five compounds were activating the pathway non-specifically by themselves producing free radicals rather than disrupting the protein-protein interaction. The remaining two compounds are currently being characterised further.