PUBLICATION
Identification of compounds that inhibit the binding of Keap1a/Keap1b Kelch DGR domain with Nrf2 ETGE/DLG motifs in zebrafish
- Authors
- Raghunath, A., Nagarajan, R., Sundarraj, K., Palanisamy, K., Perumal, E.
- ID
- ZDB-PUB-190313-10
- Date
- 2019
- Source
- Basic & Clinical Pharmacology & Toxicology 125(3): 259-270 (Journal)
- Registered Authors
- Azhwar, Raghunath
- Keywords
- Keap1-Nrf2-ARE pathway, esculin, non-covalent interaction, oxidative stress, protein-protein interaction, zebrafish
- MeSH Terms
-
- Animals
- Antioxidants/pharmacology*
- Carrier Proteins/antagonists & inhibitors
- Carrier Proteins/genetics
- Carrier Proteins/metabolism
- Drug Discovery*
- Embryo, Nonmammalian
- Esculin/pharmacology
- Lethal Dose 50
- Ligands
- Molecular Docking Simulation
- NF-E2-Related Factor 2/agonists*
- NF-E2-Related Factor 2/metabolism
- Oxidative Stress/drug effects
- Phylogeny
- Protein Binding/drug effects
- Protein Interaction Domains and Motifs/drug effects*
- Protein Interaction Domains and Motifs/genetics
- Transcription, Genetic/drug effects
- Zebrafish
- Zebrafish Proteins/agonists*
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 30861618 Full text @ Basic Clin. Pharmacol. Toxicol.
Citation
Raghunath, A., Nagarajan, R., Sundarraj, K., Palanisamy, K., Perumal, E. (2019) Identification of compounds that inhibit the binding of Keap1a/Keap1b Kelch DGR domain with Nrf2 ETGE/DLG motifs in zebrafish. Basic & Clinical Pharmacology & Toxicology. 125(3):259-270.
Abstract
The Keap1-Nrf2-ARE system serves as a premier defence mechanism to curb oxidative stress, which remains as one of the major causes of ageing and pathogenesis in various diseases. Nrf2 is the principal master regulator of the cellular defence system and its activation remains the prospective therapeutic approach against chronic diseases. One of the recent strategies is to disrupt Keap1-Nrf2 protein-protein interaction (PPI) that alters the docking of Keap1 with Nrf2 by compounds occupying a position in the Keap1 blocking the interface with Nrf2. In this study, we made an attempt to identify the compounds with anticancer, antioxidant and anti-inflammatory properties to disrupt Keap1a/b-Nrf2 PPI through in silico molecular docking in zebrafish. The phylogenetic analysis of Keap1 proteins revealed the existence of orthologous Keap1-Nrf2-ARE system in lower vertebrates that includes zebrafish. The DGR domains of zebrafish Keap1a and Keap1b were modelled with Modeller 9.19 using Keap1 of Mus musculus (5CGJ) as template. Based on the docking calculations, top hit compounds were identified to disrupt both Keap1a and Keap1b interaction with Nrf2 which includes quercetin 3,4'-diglucoside, flavin adenine dinucleotide disodium salt hydrate, salvianolic acid-A, tunicamycin and esculin. The LC50 of esculin in 3 dpf zebrafish larvae is 5 mM and the qRT-PCR results showed that esculin significantly increased the transcription of Nrf2 target genes - Gstpi, Nqo1, Hmox1a, and Prdx1 in 3 dpf zebrafish larvae. These potential hits could serve as safer Nrf2 activators due to their non-covalent disruption of Keap1-Nrf2 PPI and be developed into efficacious preventive/therapeutic agents for various diseases. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping