Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
J Biomol Struct Dyn. 2021 Feb;39(2):681-690. doi: 10.1080/07391102.2020.1715262. Epub 2020 Feb 12.
One of the important molecular targets for antitumor drug discovery is the polyadenosine diphosphate-ribose polymerase-1 (PARP1) enzyme. It is linked with various biological functions including DNA repair and apoptosis. It is primarily a nuclear enzyme linked to chromatin, which is activated by DNA damage. Improved expression of PARP1 in melanomas, breast cancer, lung cancer and other neoplastic diseases is often observed. A tremendous PARP research concerning cancer and ischemia is progressing very rapidly. There are currently four PARP1 inhibitors approved by the FDA on the market, namely Olaparib, Rucaparib, Niraparib and Talazoparib. All of these molecules are non-selective inhibitors of PARP1. Currently there is an urgent need for novel and selective PARP1 inhibitors. In this work, asmall molecule database (Specs SC) were used to identify the new selective lead inhibitors of PARP1. Piperazine scaffold is an important fragment that is used in many currently used FDA approved drugs in different diseases including PARP1 inhibitor Olaparib. Thus, based on text mining studies, 4674 compounds thatinclude piperazine fragments were identified and virtually screened at the binding pocket of target protein PARP1. Compounds that have high docking scores were used in molecular dynamics (MD) simulations. Free energy calculations were also performed to compare the predicted binding energies with known PARP1 inhibitors. The critical amino acid interactions of these newly identified hits in the binding pocket were also investigated in detail for better understanding of the structural features required for next generation PARP1 inhibitors. Thus, here together with combination of text-mining and integrated molecular modeling approaches, we identified novel piperazine-based hits against PARP1 enzyme.Communicated by Ramaswamy H. Sarma.
聚腺苷二磷酸核糖聚合酶 1（PARP1）是抗肿瘤药物发现的重要分子靶标之一。它与包括 DNA 修复和细胞凋亡在内的各种生物学功能有关。它主要是一种与染色质相关的核酶，可被 DNA 损伤激活。在黑色素瘤、乳腺癌、肺癌和其他肿瘤性疾病中，通常观察到 PARP1 的表达增加。针对癌症和缺血的大量 PARP 研究正在迅速推进。目前，FDA 批准了四种 PARP1 抑制剂上市，即奥拉帕利、鲁卡帕利、尼拉帕利和他拉唑帕利。所有这些分子都是 PARP1 的非选择性抑制剂。目前迫切需要新型和选择性 PARP1 抑制剂。在这项工作中，使用小分子数据库（Specs SC）来鉴定 PARP1 的新型选择性先导抑制剂。哌嗪骨架是一个重要的片段，用于许多目前在不同疾病中使用的 FDA 批准药物，包括 PARP1 抑制剂奥拉帕利。因此，基于文本挖掘研究，鉴定了包含哌嗪片段的 4674 种化合物，并在目标蛋白 PARP1 的结合口袋中进行了虚拟筛选。具有高对接分数的化合物用于分子动力学（MD）模拟。还进行了自由能计算，以比较预测的结合能与已知的 PARP1 抑制剂。还详细研究了这些新鉴定的结合口袋中命中物的关键氨基酸相互作用，以更好地理解下一代 PARP1 抑制剂所需的结构特征。因此，在这里，我们通过文本挖掘和综合分子建模方法相结合，鉴定了针对 PARP1 酶的新型基于哌嗪的命中物。由 Ramaswamy H. Sarma 交流。
