Virtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain.

Abstract

Overexpression of the CREB-binding protein (CBP), a bromodomain-containing transcription coactivator involved in a variety of cellular processes, has been observed in several types of cancer with a correlation to aggressiveness. We have screened a library of nearly 1500 fragments by high-throughput docking into the CBP bromodomain followed by binding energy evaluation using a force field with electrostatic solvation. Twenty of the 39 fragments selected by virtual screening are positive in one or more ligand-observed nuclear magnetic resonance (NMR) experiments. Four crystal structures of the CBP bromodomain in complex with in silico screening hits validate the pose predicted by docking. Thus, the success ratio of the high-throughput docking procedure is 50% or 10% if one considers the validation by ligand-observed NMR spectroscopy or X-ray crystallography, respectively. Compounds 1 and 3 show favorable ligand efficiency in two different in vitro binding assays. The structure of the CBP bromodomain in the complex with the brominated pyrrole 1 suggests fragment growing by Suzuki coupling.

• Authors: Dimitrios Spiliotopoulos, Jian Zhu, Eike-Christian Wamhoff, Nicholas Deerain, Jean-Rémy Marchand, Jonas Aretz, Christoph Rademacher, Amedeo Caflisch
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 27 Issue 11 Pg. 2472-2478 (06 01 2017) ISSN: 1464-3405 [Electronic] England
• PMID: 28410781 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Benzene Derivatives
• Heterocyclic Compounds
• Ligands
• Small Molecule Libraries
• CREB-Binding Protein

Topics

• Benzene Derivatives (chemistry)
• CREB-Binding Protein (antagonists & inhibitors, chemistry)
• Computer Simulation
• Crystallography, X-Ray
• Drug Discovery
• Heterocyclic Compounds (chemistry)
• High-Throughput Screening Assays
• Hydrogen Bonding
• Ligands
• Magnetic Resonance Spectroscopy
• Molecular Docking Simulation
• Protein Domains
• Small Molecule Libraries