9ey4

The FK1 domain of FKBP51 in complex with (3S,11S)-12-((3,5-dichlorophenyl)sulfonyl)-5-oxo-11-vinyldecahydro-1H-6,10-epiminopyrrolo[1,2-a]azonine-3-carboxamide

spinqualitylabelsall models 9ey4, resolution 1.16Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9ey4 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.16Å Ligands: A1H78 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Access to small, rigid, and sp3-rich molecules is a major limitation in the drug discovery for challenging protein targets. FK506-binding proteins hold high potential as drug targets or enablers of molecular glues but are fastidious in the chemotypes accepted as ligands. We here report an enantioselective synthesis of a highly rigidified pipecolate-mimicking tricyclic scaffold that precisely position functional groups for interacting with FKBPs. This was enabled by a 14-step gram-scale synthesis featuring anodic oxidation, stereospecific vinylation, and N-acyl iminium cyclization. Structure-based optimization resulted in the discovery of FKBP inhibitors with picomolar biochemical and subnanomolar cellular activity that represent the most potent FKBP ligands known to date. Structure-Based Design of Ultrapotent Tricyclic Ligands for FK506-Binding proteins.,Krajczy P, Meyners C, Repity M, Hausch F Chemistry. 2024 Jun 5:e202401405. doi: 10.1002/chem.202401405. PMID:38837733 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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