title: Fragment screening and druggability assessment for the CBP/p300 KIX domain through protein-observed 19F NMR spectroscopy.
abstract: (19)F NMR spectroscopy of labeled proteins is a sensitive method for characterizing structure, conformational dynamics, higher-order assembly, and ligand binding. Fluorination of aromatic side chains has been suggested as a labeling strategy for small-molecule ligand discovery for protein-protein interaction interfaces. Using a model transcription factor binding domain of the CREB binding protein (CBP)/p300, KIX, we report the first full small-molecule screen using protein-observed (19)F NMR spectroscopy. Screening of 508 compounds and validation by (1)H-(15)N HSQC NMR spectroscopy led to the identification of a minimal pharmacaphore for the MLL-KIX interaction site. Hit rate analysis for the CREB-KIX and MLL-KIX sites provided a metric to assess the ligandability or "druggability" of each interface informing future medicinal chemistry efforts. The structural information from the simplified spectra and data collection speed, affords a new screening tool for analysis of protein interfaces and discovery of small molecules.
authors: Department of Chemistry, University of Minnesota, 207 Pleasant St. SE, Twin Cities (USA).
authors: Clifford T
authors: CT
authors: Gee
authors: Edward J
authors: EJ
authors: Koleski
authors: William C K
authors: WC
authors: Pomerantz
mesh_terms: D000818:Animals; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000737:chemistry* / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000737:chemistry* / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry; D006801:Humans; D008024:Ligands; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D005461:Fluorine; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: biomolecular NMR; fluorine; fragment screening; protein-protein interactions; transcription
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