Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Bioorg Med Chem Lett. 2013 Nov 1;23(21):5790-4. doi: 10.1016/j.bmcl.2013.09.007. Epub 2013 Sep 10.
Poly(ADP-ribose)polymerase-1 (PARP-1) is an abundant and ubiquitous chromatin-bound nuclear protein. PARP-1, a DNA repair enzyme, has been in the limelight as a chemotherapeutic target. In this study, we demonstrated the successful use of structure-based virtual screening to identify inhibitors of PARP-1 from Otava databases comprised of nearly 260,000 compounds. Five novel inhibitors belonging to thienopyrimidinone, isoquinolinoquinazolinone, pyrroloquinazolinone, and cyclopentenothienopyrimidinone scaffolds revealed inhibitory potencies with IC50 values ranged from 9.57μM to 0.72μM. Structural features relevant to the activity of these novel compounds within the active site of PARP-1 are discussed in detail and will guide future SAR investigation on these scaffolds.
聚（ADP-核糖）聚合酶-1（PARP-1）是一种丰富且普遍存在的染色质结合核蛋白。PARP-1 是一种 DNA 修复酶，作为一种化疗靶点备受关注。在这项研究中，我们成功地使用基于结构的虚拟筛选，从包含近 26 万种化合物的 Otava 数据库中鉴定出 PARP-1 的抑制剂。属于噻吩并嘧啶酮、异喹啉喹唑啉酮、吡咯并喹唑啉酮和环戊烯噻吩并嘧啶酮骨架的五种新型抑制剂具有抑制活性，IC50 值范围为 9.57μM 至 0.72μM。详细讨论了这些新型化合物在 PARP-1 活性位点中的活性相关结构特征，这将为这些骨架的进一步 SAR 研究提供指导。
