Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening

被引：35

作者：

Andersson, C. David ^{[1
]}

Karlberg, Tobias ^{[2
]}

Ekblad, Torun ^{[2
]}

Lindgren, Anders E. G. ^{[1
]}

Thorsell, Ann-Gerd ^{[2
]}

Spjut, Sara ^{[1
]}

Uciechowska, Urszula ^{[1
]}

Niemiec, Moritz S. ^{[1
]}

Wittung-Stafshede, Pernilla ^{[1
]}

Weigelt, Johan ^{[2
]}

Elofsson, Mikael ^{[1
]}

Schuler, Herwig ^{[2
]}

Linusson, Anna ^{[1
]}

机构：

[1] Umea Univ, Dept Chem, SE-90187 Umea, Sweden

[2] Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 17期

基金：

瑞典研究理事会;

关键词：

POLY(ADP-RIBOSE) POLYMERASE; STRUCTURAL BASIS; GENETIC ALGORITHM; MOLECULAR DOCKING; SCORING FUNCTIONS; CRYSTAL-STRUCTURE; CATALYTIC DOMAIN; PROTEIN; INHIBITOR; STRATEGIES;

D O I：

10.1021/jm300746d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：7706 / 7718

页数：13

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