Abstract
Due to role of the Keap1–Nrf2 protein–protein interaction (PPI) in protecting cells from oxidative stress, the development of small molecule inhibitors that inhibit this interaction has arisen as a viable approach to combat maladies caused by oxidative stress, such as cancers, neurodegenerative disease and diabetes. To obtain specific and genuine Keap1–Nrf2 inhibitors, many efforts have been made towards developing new screening approaches. However, there is no inhibitor for this target entering the clinic for the treatment of human diseases. New strategies to identify novel bioactive compounds from large molecular databases and accelerate the developmental process of the clinical application of Keap1–Nrf2 protein–protein interaction inhibitors are greatly needed. In this review, we have summarized virtual screening and other methods for discovering new lead compounds against the Keap1–Nrf2 protein–protein interaction. We also discuss the advantages and limitations of different strategies, and the potential of this PPI as a drug target in disease therapy.
Highlights
Oxidative stress is associated with the pathogenesis of cancers, neurodegenerative diseases, inflammatory diseases, cardiovascular diseases and aging, which are major causes of human death [1]
nuclear factor erythrocyte 2 related factor 2 (Nrf2) holds two binding regions, These two motifs are included into the polylysine region, which is indispensable for ubiquitination in ETGE and DLG, which interact with the C-terminal domain(DC)region of Kelch-like ECH-associated protein 1 (Keap1) with distinct the so-called thispolylysine model, theregion, higher-affinity
The main synthesized molecules to target the domain of Keap1, an in ID: silico experiment wasinteractions conducted observed between the native ligand and the protein target were arene–cation interactions withligand
Summary
Oxidative stress is associated with the pathogenesis of cancers, neurodegenerative diseases, inflammatory diseases, cardiovascular diseases and aging, which are major causes of human death [1]. Neh is a basic leucine zipper motif that allows for heterodimer an adapter for the Cullin (Cul3)-based ubiquitin E3 ligase complex [14] In this ternary complex, Keap formation to DNA, via partnering with small muscle decidual fibrosarcoma (Maf) protein or another nottranscriptional only bridges Cul and Nrf together via protein–protein interactions (PPI), and functions as a partner [20]. Neh is aKeap basic has leucine zipper motif that allows region for heterodimer the broad-complex, and bricsmall a brac (BTB)decidual domain, fibrosarcoma an intervening region (IVR)orwith a formation to DNA, viatramtrack partnering with muscle (Maf) protein another double glycine region (DGR), multiple cysteines, and a. DGR and CTR domains are together called the DC domains and bind the CREB-binding protein (CBP), a transcriptional coactivator that controls the transcription activity of to Neh of Nrf to regulate themotif interaction.
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