title: Discovery of potent, novel Nrf2 inducers via quantum modeling, virtual screening, and in vitro experimental validation.
abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is the master transcription factor of the antioxidant response element pathway, coordinating the induction of detoxifying and antioxidant enzymes. Nrf2 is normally sequestered in the cytoplasm by Kelch-like ECH-associating protein 1 (Keap1). To identify novel small molecules that will disturb Nrf2-Keap1 binding and promote activation of the Nrf2- antioxidant response element pathway, we generated a quantum model based on the structures of known Nrf2- antioxidant response element activators. We used the quantum model to perform in silico screening on over 18 million commercially available chemicals to identify the structures predicted to activate the Nrf2- antioxidant response element pathway based on the quantum model. The top hits were tested in vitro, and half of the predicted hits activated the Nrf2-antioxidant response element pathway significantly in primary cell culture. In addition, we identified a new family of Nrf2-antioxidant response element-activating structures that all have comparable activity to tBHQ and protect against oxidative stress and dopaminergic toxins in vitro. The improved ability to identify potent activators of Nrf2 through the combination of in silico and in vitro screening described here improves the speed and cost associated with screening Nrf2-antioxidant response element -activating compounds for drug development.
authors.affiliation: Divison of Pharmaceutical Sciences, University of Wisconsin, Madison, WI, USA.
authors.forename: Tracy P
authors.initials: TP
authors.lastname: Williamson
authors.forename: Sara
authors.initials: S
authors.lastname: Amirahmadi
authors.forename: Gururaj
authors.initials: G
authors.lastname: Joshi
authors.forename: Nikola K
authors.initials: NK
authors.lastname: Kaludov
authors.forename: Martin N
authors.initials: MN
authors.lastname: Martinov
authors.forename: Delinda A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D051379:Mice; D008956:Models, Chemical; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D011789:Quantum Theory; D020218:Response Elements; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D054852:Small Molecule Libraries