CPUY192018, a potent inhibitor of the Keap1-Nrf2 protein-protein interaction, alleviates renal inflammation in mice by restricting oxidative stress and NF-κB activation

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.

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Identification of Novel Nrf2 Activator via Protein-ligand Interactions as Remedy for Oxidative Stress in Diabetes Mellitus

Letters in Drug Design & Discovery ◽

10.2174/1570180818666210413131108 ◽

2021 ◽

Vol 18 ◽

Author(s):

Afolashade Toritseju Onunkun ◽

Opeyemi Iwaloye ◽

Olusola Olalekan Elekofehinti

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Free Energy ◽

Protein Interaction ◽

Binding Free Energy ◽

Natural Compounds ◽

Protein Protein Interaction ◽

Glide Docking ◽

Adme Properties ◽

Nrf2 Protein

Background: Oxidative stress is a significant player in the pathogenesis of diabetes mellitus and the Kelch-like ECH-associated protein1/nuclear factor erythroid 2-related factor 2/antioxidant response element (Keap1/Nrf2/ARE) signaling pathway serves as the essential defense system to mitigate oxidative stress. Nrf2 is responsible for the mitigation of oxidative stress while Keap1 represses Nrf2’s activation upon binding. Identification of Nrf2 activators has started to pick up enthusiasm as they can be used as therapeutic agents against diabetes mellitus. One of the ongoing mechanisms in the activation of Nrf2 is to disrupt Keap1/Nrf2 protein-protein interaction. This study aimed at using computational analysis to screen natural compounds capable of inhibiting Keap1/Nrf2 protein-protein interaction. Methods: A manual curated library of natural compounds was screened against crystal structure of Keap1 using glide docking algorithm. Binding free energy of the docked complexes, and adsorption, digestion, metabolism and excretion (ADME) properties were further employed to identify the hit compounds. The bioactivity of the identified hit against Keap1 was predicted using quantitative structure-activity relationship (QSAR) model. Results: A total of 7 natural compounds (Compound 222, 230, 310, 208, 210, 229 and 205) identified from different medicinal plants were found to be potent against Keap1 based on their binding affinity and binding free energy. The internal validated model kpls_radial_30 with R2 of 0.9109, Q2 of 0.7287 was used to predict the compounds’ bioactivities. Compound 205 was considered as the ideal drug candidate because it showed moderation for ADME properties, had predicted pIC50 of 6.614 and obeyed Lipinski’s rule of five. Conclusion: This study revealed that Compound 205, a compound isolated from Amphipterygium adstringens is worth considering for further experimental analysis.

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