Fragment screening and druggability assessment for the CBP/p300 KIX domain through protein-observed 19F NMR spectroscopy

Clifford T. Gee, Edward J. Koleski, William C.K. Pomerantz

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

19F 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 19F NMR spectroscopy. Screening of 508 compounds and validation by 1H-15N 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. A full small-molecule screen has been achieved using protein-observed 19F NMR (PrOF NMR) spectroscopy of a model transcription factor binding domain of the CREB binding protein (CBP)/p300, KIX. This study demonstrates the applicability of PrOF NMR as a tool for library screening, ligand discovery, and druggability assessment.

Original languageEnglish (US)
Pages (from-to)3735-3739
Number of pages5
JournalAngewandte Chemie - International Edition
Volume54
Issue number12
DOIs
StatePublished - Mar 16 2015

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Keywords

  • biomolecular NMR
  • fluorine
  • fragment screening
  • protein-protein interactions
  • transcription

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