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.

SUBMITTER: Gee CT 

PROVIDER: S-EPMC4423596 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature