title: Discovery of ligands for ADP-ribosyltransferases via docking-based virtual screening.
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 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.
authors: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
authors: C David
authors: CD
authors: Andersson
authors: Tobias
authors: T
authors: Karlberg
authors: Torun
authors: T
authors: Ekblad
authors: Anders E G
authors: AE
authors: Lindgren
authors: Ann-Gerd
authors: AG
authors: Thorsell
authors: Sara
authors: S
authors: Spjut
authors: Urszula
authors: U
authors: Uciechowska
authors: Moritz S
authors: MS
authors: Niemiec
authors: Pernilla
authors: P
authors: Wittung-Stafshede
authors: Johan
authors: J
authors: Weigelt
authors: Mikael
authors: M
authors: Elofsson
authors: Herwig
authors: H
authors: Schüler
authors: Anna
authors: A
authors: Linusson
mesh_terms: D036002:ADP Ribose Transferases / Q000378:metabolism*; D055808:Drug Discovery; D008024:Ligands; D008958:Models, Molecular
chemical_list: D008024:Ligands; D036002:ADP Ribose Transferases