Binding Mode and Structure–Activity Relationships around Direct Inhibitors of the Nrf2–Keap1 Complex |
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| Authors: | 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 Dr Jean‐Philippe Courade |
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| Affiliation: | 1. UCB Pharma, UCB NewMedicines, Chemin du Foriest, 1420 Braine‐l'Alleud (Belgium);2. Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14?4RZ (UK);3. UCB Pharma, UCB NewMedicines, 208 Bath Road, Slough, Berkshire SL1?3WE (UK);4. CEM Microwave Technology Ltd. 2 Middle Slade, Buckingham, Buckinghamshire MK18?1WA (UK) |
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| Abstract: | 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. |
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| Keywords: | CNS co‐crystal structures docking Keap1 Nrf2 structure– activity relationships |
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