Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
J Med Chem. 2012 Sep 13;55(17):7706-18. doi: 10.1021/jm300746d. Epub 2012 Aug 20.
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.
依赖于烟酰胺腺嘌呤二核苷酸 (NAD(+)) 的二价阴离子核糖基转移酶（ADP-ribosyltransferases，ARTDs）家族是一类酶，可通过将烟酰胺腺嘌呤二核苷酸（NAD(+)) 作为共底物将 ADP-ribose 单位转移到底物蛋白上。它们在染色质重塑和 DNA 修复中具有明确的作用，并且 ARTD1 和 2（PARP1 和 2）的抑制剂目前正在临床试验中用于癌症的治疗。大多数其他 ARTD 的详细功能仍然未知。通过使用虚拟筛选，我们鉴定了 ARTD7（PARP15/BAL3）和 ARTD8（PARP14/BAL2）的小分子配体。热移测定证实，属于八个结构类别的 16 种化合物与 ARTD7/ARTD8 结合。两种最有希望的命中化合物的等温热滴定法的亲和力测量证实，它们与 ARTD8 的结合在低微摩尔范围内。晶体结构显示出命中化合物在烟酰胺口袋中的锚定。这些结果为开发用于研究 ARTD7 和 ARTD8 的作用和功能的化学工具奠定了基础。
