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.
Subject(s)
Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Cytoskeletal Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Isoquinolines/pharmacology , NF-E2-Related Factor 2/antagonists & inhibitors , Phthalimides/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Kelch-Like ECH-Associated Protein 1 , Mice , Models, Molecular , Molecular Structure , Phthalimides/chemical synthesis , Phthalimides/chemistry , Structure-Activity RelationshipABSTRACT
A high-throughput screening campaign resulted in the discovery of a highly potent dual cannabinoid receptor 1 (CB1) and 2 (CB2) agonist. Following a thorough SAR exploration, a series of selective CB2 full agonists were identified.