1607007-55-5Relevant articles and documents
Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex
Jnoff, Eric,Albrecht, Claudia,Barker, John J.,Barker, Oliver,Beaumont, Edward,Bromidge, Steven,Brookfield, Frederick,Brooks, Mark,Bubert, Christian,Ceska, Tom,Corden, Vincent,Dawson, Graham,Duclos, Stephanie,Fryatt, Tara,Genicot, Christophe,Jigorel, Emilie,Kwong, Jason,Maghames, Rosemary,Mushi, Innocent,Pike, Richard,Sands, Zara A.,Smith, Myron A.,Stimson, Christopher C.,Courade, Jean-Philippe
supporting information, p. 699 - 705 (2014/05/06)
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. To dock or not to dock? Nrf2 has become an attractive neuroprotective target, as the Nrf2 pathway provides a natural cell defense mechanism against damage. Targeting its physiological negative modulator Keap1 with small molecules may allow Nrf2 to play its protective role. To this end, an X-ray structure of Keap1 co-crystallised with compound (S,R,S)-1 a was obtained, elucidating its binding mode, which in turn helped to drive the drug design process.
