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.
Keywords:
CNS; Keap1; Nrf2; co-crystal structures; docking; structure-activity relationships.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
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Animals
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Crystallography, X-Ray
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Cytoskeletal Proteins / antagonists & inhibitors*
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Dose-Response Relationship, Drug
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Isoquinolines / chemical synthesis
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Isoquinolines / chemistry
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Isoquinolines / pharmacology*
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Kelch-Like ECH-Associated Protein 1
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Mice
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Models, Molecular
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Molecular Structure
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NF-E2-Related Factor 2 / antagonists & inhibitors*
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Phthalimides / chemical synthesis
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Phthalimides / chemistry
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Phthalimides / pharmacology*
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Structure-Activity Relationship
Substances
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2-(1-((1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)cyclohexane-1-carboxylic acid
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Adaptor Proteins, Signal Transducing
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Cytoskeletal Proteins
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Intracellular Signaling Peptides and Proteins
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Isoquinolines
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KEAP1 protein, human
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Keap1 protein, mouse
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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Nfe2l2 protein, mouse
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Phthalimides