Binding Mode and Structure–Activity Relationships around Direct Inhibitors of the Nrf2–Keap1 Complex

作者：Eric Jnoff, Claudia Albrecht, John J. Barker, Oliver Barker, Edward Beaumont, Steven M. Bromidge, Frederick A. Brookfield, Mark Brooks, Christian Bubert, Tom Ceska, Vincent Corden, Graham Dawson, Stéphanie Duclos, Tara Fryatt, Christophe Génicot, Émilie Jigorel, Jason C. Kwong, Rosemary Maghames, Innocent Mushi, Richard K Pike, Zara A. Sands, M. A. Smith, Christopher C. Stimson, Jean‐Philippe Courade · 发表于：ChemMedChem · 年份：2014 · DOI：10.1002/cmdc.201300525 · 被引用次数：178 · 研究领域：Genomics, phytochemicals, and oxidative stress、Synthesis and Biological Evaluation、Structural and Chemical Analysis of Organic and Inorganic Compounds

An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.