ArticleBiochemistry2020
Interaction Energetics and Druggability of the Protein-Protein Interaction between Kelch-like ECH-Associated Protein 1 (KEAP1) and Nuclear Factor Erythroid 2 Like 2 (Nrf2).
Article in Biochemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 33 citations in OpenAlex.
- Chemical Profiling and Scaffold-Based Drug-Discovery Analysis of Bioactive Compounds fromJournal of chemical information and modeling · 2026Article
- In Silico Druggability Assessment ofAntibiotics (Basel, Switzerland) · 2026Article
- SMND-309 activates Nrf2 signaling to alleviate acetaminophen-induced hepatotoxicity and oxidative stress.PloS one · 2025Article
- Flavonoids Regulate Redox-Responsive Transcription Factors in Glioblastoma and Microglia.Cells · 2023Article
- Computational Prediction of Cyclic Peptide Structural Ensembles and Application to the Design of Keap1 Binders.Journal of chemical information and modeling · 2023Article
- SARS-CoV-2 infection and dysregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) pathway.Cell stress & chaperones · 2023Review
- A cell-active cyclic peptide targeting the Nrf2/Keap1 protein-protein interaction.Chemical science · 2023Article
- Phytochemical Screening and Antioxidant Potential of Selected Extracts fromPlants (Basel, Switzerland) · 2023Article
- DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- DeepCubist: Molecular Generator for Designing Peptidomimetics based on Complex three-dimensional scaffolds.Journal of computer-aided molecular design · 2023Article
- A Multifunctional (-)-Meptazinol-Serotonin Hybrid Ameliorates Oxidative Stress-Associated Apoptotic Neuronal Death and Memory Deficits via Activating the Nrf2/Antioxidant Enzyme Pathway.Oxidative medicine and cellular longevity · 2023Article
- Mapping the binding sites of challenging drug targets.Current opinion in structural biology · 2022Review
- Structure-activity relationships of 1,4-bis(arylsulfonamido)-benzene or naphthalene-N,N'-diacetic acids with varying C2-substituents as inhibitors of Keap1-Nrf2 protein-protein interaction.European journal of medicinal chemistry · 2022Article
- Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1-Nrf2 Protein-Protein Interaction.Journal of medicinal chemistry · 2022Article
- Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway.International journal of molecular sciences · 2022Article
- Astaxanthine attenuates cisplatin ototoxicityActa pharmaceutica Sinica. B · 2022Article
- Mining Natural Products for Macrocycles to Drug Difficult Targets.Journal of medicinal chemistry · 2021Article
- Fucoxanthin Prevents 6-OHDA-Induced Neurotoxicity by Targeting Keap1.Oxidative medicine and cellular longevity · 2021Article
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Authors and funding
17 authors at 3 institutions in 1 country.
Funding
Abstract
Development of small molecule inhibitors of protein-protein interactions (PPIs) is hampered by our poor understanding of the druggability of PPI target sites. Here, we describe the combined application of alanine-scanning mutagenesis, fragment screening, and FTMap computational hot spot mapping to evaluate the energetics and druggability of the highly charged PPI interface between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2 like 2 (Nrf2), an important drug target. FTMap identifies four binding energy hot spots at the active site. Only two of these are exploited by Nrf2, which alanine scanning of both proteins shows to bind primarily through E79 and E82 interacting with KEAP1 residues S363, R380, R415, R483, and S508. We identify fragment hits and obtain X-ray complex structures for three fragments via crystal soaking using a new crystal form of KEAP1. Combining these results provides a comprehensive and quantitative picture of the origins of binding energy at the interface. Our findings additionally reveal non-native interactions that might be exploited in the design of uncharged synthetic ligands to occupy the same site on KEAP1 that has evolved to bind the highly charged DEETGE binding loop of Nrf2. These include π-stacking with KEAP1 Y525 and interactions at an FTMap-identified hot spot deep in the binding site. Finally, we discuss how the complementary information provided by alanine-scanning mutagenesis, fragment screening, and computational hot spot mapping can be integrated to more comprehensively evaluate PPI druggability.
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