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Fragment Screening and Druggability Assessment for the CBP/p300 KIX Domain through Protein‐Observed 19 F NMR Spectroscopy
Author(s) -
Gee Clifford T.,
Koleski Edward J.,
Pomerantz William C. K.
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201411658
Subject(s) - druggability , chemistry , nuclear magnetic resonance spectroscopy , small molecule , spectroscopy , chemical genetics , biophysics , stereochemistry , biochemistry , physics , biology , quantum mechanics , gene
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.