In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment.
In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment.
复制标题
计算机筛选鉴定出一种新型潜在 PARP1 抑制剂，可针对癌症治疗中的合成致死率
DOI：
10.3390/ijms17020258
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发表时间：
2016-02-19
影响因子：
5.6
通讯作者：
Bao J
中科院分区：
文献类型：
--
作者：
Li J;Zhou N;Cai P;Bao J
综合致死性描述了两种不同基因或途径的缺陷共同导致细胞死亡的情况。这一概念已应用于癌症治疗的药物开发，以聚（ADP-核糖）聚合酶（PARP）抑制剂为代表。在当前的研究中，我们进行了计算筛选以发现新的 PARP 抑制剂。在分析的 11,247 种化合物中，一种天然产物 ZINC67913374 因其在模拟分析中的卓越性能而脱颖而出。与 FDA 批准的 PARP1 抑制剂奥拉帕尼相比，我们的结果表明 ZINC67913374 化合物取得了更好的网格评分 (−86.8) 和琥珀评分 (−51.42)。分子动力学模拟表明 PARP1-ZINC67913374 复合物比奥拉帕尼更稳定。 ZINC67913374的结合自由能为-177.28 kJ/mol，而奥拉帕尼的结合自由能为-159.16 kJ/mol。这些结果表明ZINC67913374以更高的亲和力与PARP1结合，这表明ZINC67913374在癌症药物开发方面具有广阔的潜力。
Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (−86.8) and amber score (−51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was −177.28 kJ/mol while that of olaparib was −159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development.