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

[Display omitted] 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 s...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2016-08, Vol.24 (16), p.3378-3386
Main Authors: Bhakkiyalakshmi, Elango, Dineshkumar, Kesavan, Karthik, Suresh, Sireesh, Dornadula, Hopper, Waheeta, Paulmurugan, Ramasamy, Ramkumar, Kunka Mohanram
Format: Article
Language:English
Subjects:
ARE
Humans
Keap1
Kelch-Like ECH-Associated Protein 1 - metabolism
Molecular docking
Molecular Docking Simulation
Molecular dynamic simulation
NF-E2-Related Factor 2 - metabolism
Nrf2
Protein Binding
Pterostilbene
Stilbenes - pharmacology
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2016.05.011