Binding Mode and Structure–Activity Relationships around Direct Inhibitors of the Nrf2–Keap1 Complex
Dr. Eric Jnoff, Dr. Claudia Albrecht, Dr. John J. Barker, Dr. Oliver Barker, Dr. Edward Beaumont, Dr. Steven Bromidge, Dr. Frederick Brookfield, Dr. Mark Brooks, Dr. Christian Bubert, Dr. Tom Ceska, Vincent Corden, Dr. Graham Dawson, Dr. Stephanie Duclos, Dr. Tara Fryatt, Dr. Christophe Genicot, Dr. Emilie Jigorel, Dr. Jason Kwong, Rosemary Maghames, Innocent Mushi, Dr. Richard Pike, Dr. Zara A. Sands, Dr. Myron A. Smith, Dr. Christopher C. Stimson and Dr. Jean-Philippe Courade
Article first published online: 6 FEB 2014 | DOI: 10.1002/cmdc.201300525
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.