Pterostilbene-mediated Nrf2 activation: Mechanistic insights on Keap1:Nrf2 interface

Bioorg Med Chem. 2016 Aug 15;24(16):3378-86. doi: 10.1016/j.bmc.2016.05.011. Epub 2016 May 11.

Abstract

The discovery of Keap1-Nrf2 protein-protein interaction (PPI) inhibitors has become a promising strategy to develop novel lead molecules against variety of stress. Hence, Keap1-Nrf2 system plays an important role in oxidative/electrophilic stress associated disorders. Our earlier studies identified pterostilbene (PTS), a natural analogue of resveratrol, as a potent Nrf2 activator and Keap1-Nrf2 PPI inhibitor as assessed by luciferase complementation assay. In this study, we further identified the potential of PTS in Nrf2 activation and ARE-driven downstream target genes expression by nuclear translocation experiments and ARE-luciferase reporter assay, respectively. Further, the luciferase complementation assay identified that PTS inhibits Keap1-Nrf2 PPI in both dose and time-dependent manner. Computational studies using molecular docking and dynamic simulation revealed that PTS directly interacts with the basic amino acids of kelch domain of Keap1 and perturb Keap1-Nrf2 interaction pattern. This manuscript not only shows the binding determinants of Keap1-Nrf2 proteins but also provides mechanistic insights on Nrf2 activation potential of PTS.

Keywords: ARE; Keap1; Molecular docking; Molecular dynamic simulation; Nrf2; Pterostilbene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Molecular Docking Simulation
  • NF-E2-Related Factor 2 / metabolism*
  • Protein Binding
  • Stilbenes / pharmacology*

Substances

  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Stilbenes
  • pterostilbene