1. Discovery of Keap1-Nrf2 small-molecule inhibitors from phytochemicals based on molecular docking.
- Author
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Li M, Huang W, Jie F, Wang M, Zhong Y, Chen Q, and Lu B
- Subjects
- Animals, Antioxidants metabolism, Antioxidants toxicity, Binding Sites, Humans, Kelch-Like ECH-Associated Protein 1 metabolism, Molecular Docking Simulation, Molecular Structure, NF-E2-Related Factor 2 metabolism, PC12 Cells, Phytochemicals metabolism, Phytochemicals toxicity, Quantitative Structure-Activity Relationship, Rats, Antioxidants pharmacology, Kelch-Like ECH-Associated Protein 1 antagonists & inhibitors, NF-E2-Related Factor 2 agonists, Phytochemicals pharmacology, Protein Binding drug effects
- Abstract
Various phytochemicals have been reported to protect against oxidative stress. However, the mechanism underlying has not been systematically evaluated, which limited their application in disease treatment. Nuclear factor erythroid 2-related factor 2 (Nrf2), a central transcription factor in oxidative stress response related to numerous diseases, is activated after dissociating from the cytoskeleton-anchored Kelch-like ECH-associated protein 1 (Keap1). The Keap1-Nrf2 protein-protein interaction has become an important drug target. This study was designed to clarify whether antioxidantive phytochemicals inhibit the Keap1-Nrf2 protein-protein interaction and activate the Nrf2-ARE signaling pathway efficiently. Molecular docking and 3D-QSAR were applied to evaluate the interaction effects between 178 antioxidant phytochemicals and the Nrf2 binding site in Keap1. The Nrf2 activation effect was tested on a H
2 O2 -induced oxidative-injured cell model. Results showed that the 178 phytochemicals could be divided into high-, medium-, and low-total-score groups depending on their binding affinity with Keap1, and the high-total-score group consisted of 24 compounds with abundant oxygen or glycosides. Meanwhile, these compounds could bind with key amino acids in the structure of the Keap1-Nrf2 interface. Compounds from high-total-score group show effective activation effects on Nrf2. In conclusion, phytochemicals showed high binding affinity with Keap1 are promising new Nrf2 activators., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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