title: Rapid identification of Keap1-Nrf2 small-molecule inhibitors through structure-based virtual screening and hit-based substructure search.
abstract: In this study, rapid structure-based virtual screening and hit-based substructure search were utilized to identify small molecules that disrupt the interaction of Keap1-Nrf2. Special emphasis was placed toward maximizing the exploration of chemical diversity of the initial hits while economically establishing informative structure-activity relationship (SAR) of novel scaffolds. Our most potent noncovalent inhibitor exhibits three times improved cellular activation in Nrf2 activation than the most active noncovalent Keap1 inhibitor known to date.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Narayanapillai
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
authors.forename: Yuk Yin
authors.initials: YY
authors.lastname: Sham
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
mesh_terms: D021581:Active Transport, Cell Nucleus; D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D003198:Computer Simulation; D062126:Databases, Chemical; D015195:Drug Design; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D016716:PC12 Cells; D011485:Protein Binding; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D001555:Benzene Derivatives; D005663:Furans; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D009281:Naphthalenes; D011758:Pyrroles; D012333:RNA, Messenger; D013449:Sulfonamides; D013844:Thiazoles