1. Discovery of Keap1−Nrf2 small−molecule inhibitors from phytochemicals based on molecular docking
- Author
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Baiyi Lu, Fan Jie, Qi Chen, Li Maiquan, Mengmeng Wang, Weisu Huang, and Yongheng Zhong
- Subjects
Antioxidant ,NF-E2-Related Factor 2 ,medicine.medical_treatment ,Phytochemicals ,Quantitative Structure-Activity Relationship ,Keap1−Nrf2 ,Toxicology ,medicine.disease_cause ,PC12 Cells ,environment and public health ,Article ,Antioxidants ,03 medical and health sciences ,0404 agricultural biotechnology ,medicine ,Animals ,Humans ,Binding site ,Transcription factor ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Binding Sites ,Kelch-Like ECH-Associated Protein 1 ,Molecular Structure ,04 agricultural and veterinary sciences ,General Medicine ,respiratory system ,040401 food science ,KEAP1 ,Small molecule ,Rats ,Amino acid ,Molecular Docking Simulation ,chemistry ,Biochemistry ,3D−QSAR CoMFA ,Molecular docking ,Signal transduction ,Oxidative stress ,Protein Binding ,Food Science - 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 H2O2−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., Highlights • 178 phytochemicals were collected and the Keap1-binding-affinity was estimated. • 24 compounds with high Keap1-binding-affinity was obtained. • Compounds with high Keap1-binding-affinity effectively activated Nrf2.
- Published
- 2019