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Discovery of ligands for ADP-ribosyltransferases via docking-based virtual screening

Andersson, C David ; Karlberg, Tobias LU ; Ekblad, Torun ; Lindgren, Anders E G ; Thorsell, Ann-Gerd ; Spjut, Sara ; Uciechowska, Urszula ; Niemiec, Moritz S ; Wittung-Stafshede, Pernilla and Weigelt, Johan , et al. (2012) In Journal of Medicinal Chemistry 55(17). p.18-7706
Abstract

The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyzes the transfer of ADP-ribose units onto substrate proteins by using nicotinamide adenine dinucleotide (NAD(+)) as a cosubstrate. They have a documented role in chromatin remodelling and DNA repair, and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. By using virtual screening, we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers... (More)

The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyzes the transfer of ADP-ribose units onto substrate proteins by using nicotinamide adenine dinucleotide (NAD(+)) as a cosubstrate. They have a documented role in chromatin remodelling and DNA repair, and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. By using virtual screening, we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.

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publishing date
type
Contribution to journal
publication status
published
keywords
ADP Ribose Transferases/metabolism, Drug Discovery, Ligands, Models, Molecular
in
Journal of Medicinal Chemistry
volume
55
issue
17
pages
13 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:84866316284
  • pmid:22823910
ISSN
1520-4804
DOI
10.1021/jm300746d
language
English
LU publication?
no
id
805d1ba7-cc50-49ab-a36f-2b15155bd88b
date added to LUP
2024-11-21 17:57:28
date last changed
2025-07-19 00:24:43
@article{805d1ba7-cc50-49ab-a36f-2b15155bd88b,
  abstract     = {{<p>The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyzes the transfer of ADP-ribose units onto substrate proteins by using nicotinamide adenine dinucleotide (NAD(+)) as a cosubstrate. They have a documented role in chromatin remodelling and DNA repair, and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. By using virtual screening, we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.</p>}},
  author       = {{Andersson, C David and Karlberg, Tobias and Ekblad, Torun and Lindgren, Anders E G and Thorsell, Ann-Gerd and Spjut, Sara and Uciechowska, Urszula and Niemiec, Moritz S and Wittung-Stafshede, Pernilla and Weigelt, Johan and Elofsson, Mikael and Schüler, Herwig and Linusson, Anna}},
  issn         = {{1520-4804}},
  keywords     = {{ADP Ribose Transferases/metabolism; Drug Discovery; Ligands; Models, Molecular}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{17}},
  pages        = {{18--7706}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Discovery of ligands for ADP-ribosyltransferases via docking-based virtual screening}},
  url          = {{http://dx.doi.org/10.1021/jm300746d}},
  doi          = {{10.1021/jm300746d}},
  volume       = {{55}},
  year         = {{2012}},
}