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

TitleVirtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain
Publication TypeJournal Article
Year of Publication2017
AuthorsSpiliotopoulos D., Zhu J., Wamhoff E.-C., Deerain N., Marchand J.-R., Aretz J., Rademacher C., Caflisch A.
JournalBioorganic & Medicinal Chemistry Letters
Volume27
Start Page2472
Issue11
Pagination2472-2478
Date Published2017 Jun 01
Type of ArticleResearch Article
ISSN1464-3405
Keywordsbromodomains, CREB-Binding Protein, Drug Design, Drug Discovery, fragment library, NMR, Virtual Screening
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.

DOI10.1016/j.bmcl.2017.04.001
pubindex

0221

Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID28410781
Highlight Role: 
Drug Design