Structural insights for peptide and small molecules based drug discovery targeting the KEAP1 Kelch domain: A review

The KEAP1-Nrf2 pathway plays a pivotal role in redox homeostasis and cellular stress. Abnormal regulation of this pathway results in neurodegenerative diseases, including Alzheimer's Disease and Parkinson's Disease, cancer and diabetes. Targeting the KEAP1 Kelch domain presents a promising therapeutic strategy to regulate Nrf2 activity. Structural insights acquired from macromolecular crystallography have enabled the development of potent inhibitors disrupting the KEAP1-Nrf2 interaction. This article focuses exclusively on compiling studies of the 112 KEAP1 structures co-crystallized with peptides and small molecule ligands over the last 20 years, investigating interactions that govern inhibitory potency. After a thorough review, small molecule ligands have been classified according to their chemical structures, including naphthalene, isoquinoline, benzotriazole, pyrazole, and azabicyclic, along with their biological efficacies to investigate the decisive interactions at the orthosteric site. Among all the reported PDB records of KEAP1, hydrogen bonding, cation-π, π-π stacking, and salt-bridge interactions predominantly contribute to stabilizing protein-ligand complexes. These insights will pave the way for the design and development of selective peptide and small molecule-based ligands for regulating the KEAP1-Nrf2 pathway, providing breakthroughs for the management of various diseases.