Related ArticlesVirtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain.
Bioorg Med Chem Lett. 2017 Apr 04;:
Authors: Spiliotopoulos D, Zhu J, Wamhoff EC, Deerain N, Marchand JR, Aretz J, Rademacher C, Caflisch A
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.
PMID: 28410781 [PubMed - as supplied by publisher]
[NMR paper] Protein-templated fragment ligations - from molecular recognition to drug discovery
Protein-templated fragment ligations - from molecular recognition to drug discovery
The understanding and manipulation of molecular recognition events is the key to modern approaches in drug discovery. Protein-templated fragment ligation is a novel concept to support drug discovery and can help to improve the efficacy of already existing protein ligands. Protein-templated fragment ligations are chemical reactions between small molecules ("fragments") that utilize a protein´s surface as a template to combine and to form a protein ligand with increased binding affinity. The...
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[NMR paper] Applications of (19)F-NMR in Fragment-Based Drug Discovery.
Applications of (19)F-NMR in Fragment-Based Drug Discovery.
Related Articles Applications of (19)F-NMR in Fragment-Based Drug Discovery.
Molecules. 2016;21(7)
Authors: Norton RS, Leung EW, Chandrashekaran IR, MacRaild CA
Abstract
(19)F-NMR has proved to be a valuable tool in fragment-based drug discovery. Its applications include screening libraries of fluorinated fragments, assessing competition among elaborated fragments and identifying the binding poses of promising hits. By observing fluorine in both the ligand and the...
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[NMR paper] Process of Fragment-Based Lead Discovery-A Perspective from NMR.
Process of Fragment-Based Lead Discovery-A Perspective from NMR.
Related Articles Process of Fragment-Based Lead Discovery-A Perspective from NMR.
Molecules. 2016;21(7)
Authors: Ma R, Wang P, Wu J, Ruan K
Abstract
Fragment-based lead discovery (FBLD) has proven fruitful during the past two decades for a variety of targets, even challenging protein-protein interaction (PPI) systems. Nuclear magnetic resonance (NMR) spectroscopy plays a vital role, from initial fragment-based screening to lead generation, because of its power...
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[NMR paper] Discovery of New E-Selectin Inhibitors by Virtual Screening, Fluorescence Binding Assays, and STD NMR Experiments.
Discovery of New E-Selectin Inhibitors by Virtual Screening, Fluorescence Binding Assays, and STD NMR Experiments.
Discovery of New E-Selectin Inhibitors by Virtual Screening, Fluorescence Binding Assays, and STD NMR Experiments.
ChemMedChem. 2016 Mar 21;
Authors: Barra PA, Jiménez VA, Gavin JA, Daranas AH, Alderete JB
Abstract
E-selectin is an endothelial protein that participates in the adhesion of metastatic cancer cells, and is therefore a relevant target for antitumor therapeutic intervention. In this work, virtual...
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[NMR paper] Fragment-based drug discovery using NMR spectroscopy.
Fragment-based drug discovery using NMR spectroscopy.
Related Articles Fragment-based drug discovery using NMR spectroscopy.
J Biomol NMR. 2013 May 18;
Authors: Harner MJ, Frank AO, Fesik SW
Abstract
Nuclear magnetic resonance (NMR) spectroscopy has evolved into a powerful tool for fragment-based drug discovery over the last two decades. While NMR has been traditionally used to elucidate the three-dimensional structures and dynamics of biomacromolecules and their interactions, it can also be a very valuable tool for the reliable...
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[NMR paper] HTS by NMR of Combinatorial Libraries: A Fragment-Based Approach to Ligand Discovery.
HTS by NMR of Combinatorial Libraries: A Fragment-Based Approach to Ligand Discovery.
http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--linkinghub.elsevier.com-ihub-images-cellhub.gif Related Articles HTS by NMR of Combinatorial Libraries: A Fragment-Based Approach to Ligand Discovery.
Chem Biol. 2013 Jan 24;20(1):19-33
Authors: Wu B, Zhang Z, Noberini R, Barile E, Giulianotti M, Pinilla C, Houghten RA, Pasquale EB, Pellecchia M
Abstract
Fragment-based ligand design (FBLD) approaches have become more widely used in drug discovery...
NMR Screening and Hit Validation in Fragment Based Drug Discovery.
NMR Screening and Hit Validation in Fragment Based Drug Discovery.
Related Articles NMR Screening and Hit Validation in Fragment Based Drug Discovery.
Curr Top Med Chem. 2010 Sep 2;
Authors: Campos-Olivas R
Over the past three decades nuclear magnetic resonance spectroscopy has been developed into a mature technique for the characterization of interactions of small molecule ligands with their corresponding protein and nucleic acid receptors. In fact, a significant number of industrial and academic laboratories employ NMR for screening small...
Virtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain.
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