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-   -   [NMR paper] Fragment Screening and Druggability Assessment for the CBP/p300 KIX Domain through Protein-Observed (19) F NMR Spectroscopy. (http://www.bionmr.com/forum/journal-club-9/fragment-screening-druggability-assessment-cbp-p300-kix-domain-through-protein-observed-19-f-nmr-spectroscopy-21803/)

nmrlearner 02-05-2015 12:00 PM

Fragment Screening and Druggability Assessment for the CBP/p300 KIX Domain through Protein-Observed (19) F NMR Spectroscopy.
 
Fragment Screening and Druggability Assessment for the CBP/p300 KIX Domain through Protein-Observed (19) F NMR Spectroscopy.

Fragment Screening and Druggability Assessment for the CBP/p300 KIX Domain through Protein-Observed (19) F NMR Spectroscopy.

Angew Chem Int Ed Engl. 2015 Feb 4;

Authors: Gee CT, Koleski EJ, Pomerantz WC

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.


PMID: 25651535 [PubMed - as supplied by publisher]



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