| Literature DB >> 27312421 |
Elango Bhakkiyalakshmi1, Kesavan Dineshkumar2, Suresh Karthik1, Dornadula Sireesh3, Waheeta Hopper2, Ramasamy Paulmurugan4, Kunka Mohanram Ramkumar5.
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.Entities:
Keywords: ARE; Keap1; Molecular docking; Molecular dynamic simulation; Nrf2; Pterostilbene
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Year: 2016 PMID： 27312421 DOI： 10.1016/j.bmc.2016.05.011
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641