Poly(ADP-ribose) polymerases (PARPs), a nuclear protein belongs to a new class of drugs, which mainly target tumours with DNA repair defects. They are mainly involved in the multiple cellular processes in addition to the DNA repair process. They act directly on the base excision repair, which is considered as one of the important pathway for cell survival in breast cancer. These belong to the active members of DNA repair assembly and evolved as a key target in the anti-cancer drug discovery. 1,3,4-Oxadiazoles are also well known anticancer agents. A novel series of 1,3,4-oxadiazoles linked to Schiff bases (T1-21) were designed and subjected to In-silico analysis against PARP-1 (PDB ID:5DS3) enzyme targeting against breast cancer. Molecular docking study for the designed compounds (T1-21) was performed by In-silico ADMET screening by QikProp module, Glide module and MM-GBSA binding free energy calculations by using Schrodinger suit 2019–2. The PARP-1 enzyme shows the binding affinity against the newly designed molecules (T1-21) based on the glide scores. Compounds T21, T12 showed very good glide score by the molecular docking studies and compared with the standard Tamoxifen. The binding free energies by the MM-GBSA assay were found to be consistent. The pharmacokinetic (ADMET) parameters of all the newly designed compounds were found to be in the acceptable range. The selected 1,3,4-oxadiazole-schiff base conjugates seems to be one of the potential source for the further development of anticancer agents against PARP-1 enzyme. The results revealed that some of the compounds T21, T17, T14, T13, T12, T8 with good glide scores showed very significant activity against breast cancer

中文翻译：

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Insilico 设计、ADMET 筛选、新型 1,3,4 恶二唑连接的希夫碱作为靶向乳腺癌的 PARP-1 抑制剂的 MM-GBSA 结合自由能

聚（ADP-核糖）聚合酶（PARPs）是一种核蛋白，属于一类新的药物，主要针对具有DNA修复缺陷的肿瘤。除了 DNA 修复过程外，它们还主要参与多个细胞过程。它们直接作用于碱基切除修复，这被认为是乳腺癌细胞存活的重要途径之一。它们属于 DNA 修复组装的活跃成员，并进化为抗癌药物发现的关键目标。1,3,4-恶二唑也是众所周知的抗癌剂。设计了一系列与希夫碱 (T1-21) 相连的新型 1,3,4-恶二唑，并针对针对乳腺癌的 PARP-1 (PDB ID:5DS3) 酶进行了计算机分析。设计的化合物 (T1-21) 的分子对接研究是通过 QikProp 模块的 In-silico ADMET 筛选进行的，使用 Schrodinger 套装 2019-2 计算 Glide 模块和 MM-GBSA 结合自由能。PARP-1 酶根据滑行评分显示对新设计的分子 (T1-21) 的结合亲和力。通过分子对接研究并与标准他莫昔芬相比，化合物 T21、T12 显示出非常好的滑动评分。发现 MM-GBSA 测定的结合自由能是一致的。发现所有新设计的化合物的药代动力学 (ADMET) 参数都在可接受的范围内。所选的 1,3,4-恶二唑-席夫碱缀合物似乎是进一步开发针对 PARP-1 酶的抗癌剂的潜在来源之一。结果显示，一些具有良好滑动评分的化合物T21、T17、T14、T13、T12、T8显示出非常显着的抗乳腺癌活性