Abstract：
Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models—CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)—of pteridinone derivatives were established. The three models that were established gave Rpred2 = 0.683, Rpred 2= 0.758, and Rpred 2= 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases.
摘要：
已经在许多不同类型的癌症中发现了polo样激酶1(PLK1)的过表达。由于其在细胞增殖中的重要作用，PLK1已被确定为广谱抗癌靶标。在这项研究中,3D-QSAR,分子对接,和分子动力学（MD）模拟应用于一系列新型的蝶啶酮衍生物作为PLK1抑制剂，以发现抗癌药物候选物。在这项工作中,三种型号-CoMFA(Q²=0.67，R²=0.992)，CoMSIA/SHE（Q²=0.69，R²=0.974），并建立了蝶啶酮衍生物的CoMSIA/SEAH（Q²=0.66，R²=0.975）。建立的三个模型分别为Rpred2=0.683，Rpred＆amp;nbsp;2=0.758和Rpred＆amp;nbsp;2=0.767。因此，成功评估了三个模型的预测能力。CoMFA和CoMSIA/SEAH模型的等高线图很好地证明了不同冠军与活动之间的关系。分子对接的结果表明，残基R136，R57，Y133，L69，L82和Y139是PLK1蛋白的活性位点（PDB代码：2RKU），其中活性更强的配体可以抑制PLK1的酶。获得的分子动力学MD模拟图的结果加强了以前的分子对接结果，这表明两种抑制剂在PLK1蛋白(PDB代码:2RKU)的活性位点保持稳定50ns。最后,对两种最具活性分子的ADME-Tox特性的检查表明,分子N°28可以成为治疗前列腺癌疾病的良好候选药物.
