Abstract：
High-grade serous ovarian cancer (HGSOC) is the most malignant and ubiquitous phenotype of epithelial ovarian cancer. Originating in the fallopian tubes and rapidly spreading to the ovaries, this highly heterogeneous disease is a result of serous tubal intraepithelial carcinoma. The proteins known as poly(ADP-ribose) polymerase (PARP) aid in the development of HGSOC by repairing the cancer cells that proliferate and spread metastatically. By using molecular docking to screen 1100 marine natural products (MNPs) from different marine environments against PARP-1/2 proteins, prominent PARP inhibitors (PARPi) were identified. Four compounds, alisiaquinone A, alisiaquinone C, ascomindone D and (+)-zampanolide referred to as MNP-1, MNP-2, MNP-3 and MNP-4, respectively, were chosen based on their binding affinity towards PARP-1/2 proteins, and their bioavailability and drug-like qualities were accessed using ADMET analysis. To investigate the structural stability and dynamics of these complexes, molecular dynamics simulations were performed for 200 ns. These results were compared with the complexes of olaparib (OLA), a PARPi that has been approved by the FDA for the treatment of advanced ovarian cancer. We determined that MNP-4 exhibited stronger binding energies with PARP-1/2 proteins than OLA by using MM/PBSA calculations. Hotspot residues from PARP-1 (E883, M890, Y896, D899 and Y907) and PARP-2 (Y449, F450, A451, S457 and Y460) showed strong interactions with the compounds. To comprehend the unbinding mechanism of MNP-4 complexed with PARP-1/2, steered molecular dynamics (SMD) simulations were performed. We concluded from the free energy landscape (FEL) map that PARP-1/2 are well-stabilised when the compound MNP-4 is bound rather than being pulled away from its binding pockets. This finding provides significant evidence regarding PARPi, which could potentially be employed in the therapeutic treatment of HGSOC.Communicated by Ramaswamy H. Sarma.
摘要：
高级别浆液性卵巢癌（HGSOC）是上皮性卵巢癌中最恶性且普遍存在的表型。起源于输卵管并迅速扩散到卵巢，这种高度异质性的疾病是浆液性输卵管上皮内癌的结果。称为聚（ADP-核糖）聚合酶（PARP）的蛋白质通过修复增殖和转移扩散的癌细胞来帮助HGSOC的发展。通过分子对接筛选来自不同海洋环境的1100个海洋天然产物（MNPs），以对抗PARP-1/2蛋白，确定了突出的PARP抑制剂（PARPi）。四种化合物,阿利阿醌A,阿利阿醌C,ascomindoneD和（）-zampanolide分别称为MNP-1，MNP-2，MNP-3和MNP-4，根据它们对PARP-1/2蛋白的结合亲和力进行选择，使用ADMET分析获得了它们的生物利用度和药物样质量。为了研究这些配合物的结构稳定性和动力学，分子动力学模拟进行了200ns。将这些结果与奥拉帕尼（OLA）的配合物进行了比较，已被FDA批准用于治疗晚期卵巢癌的PARPi。通过使用MM/PBSA计算，我们确定MNP-4与PARP-1/2蛋白的结合能强于OLA。来自PARP-1（E883，M890，Y896，D899和Y907）和PARP-2（Y449，F450，A451，S457和Y460）的热点残基显示出与化合物的强相互作用。为了理解与PARP-1/2复合的MNP-4的解结合机制,进行了转向分子动力学(SMD)模拟。我们从自由能景观（FEL）图得出的结论是，当化合物MNP-4被结合而不是从其结合袋中拉出时，PARP-1/2具有良好的稳定性。这一发现提供了关于PARPi的重要证据，可能用于HGSOC的治疗。由RamaswamyH.Sarma沟通。
