Discovery of Keap1-Nrf2 small-molecule inhibitors from phytochemicals based on molecular docking.

08:00 EDT 11th August 2019 | BioPortfolio

Summary of "Discovery of Keap1-Nrf2 small-molecule inhibitors from phytochemicals based on molecular docking."

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 HO-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.


Journal Details

This article was published in the following journal.

Name: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
ISSN: 1873-6351
Pages: 110758


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Medical and Biotech [MESH] Definitions

Part of a MESSENGER RNA molecule that undergoes a conformation change upon binding a specific metabolite or other small molecule thereby regulating the messenger RNA's transcription, post-transcriptional processing, transport, translation, or stability in response to varying levels of the metabolite or other small molecule.

A small maf protein that forms dimers with NRF1 protein; NRF2 PROTEIN; and P45 NF-E2 PROTEIN. MafF complexes bind Maf recognition elements to regulate tissue-specific GENETIC TRANSCRIPTION.

A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)

A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein.

Large collections of small molecules (molecular weight about 600 or less), of similar or diverse nature which are used for high-throughput screening analysis of the gene function, protein interaction, cellular processing, biochemical pathways, or other chemical interactions.

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