Abstract：
Glioblastoma, the most severe form of brain tumor and a leading cause of death within a year of diagnosis, is characterized by excessive protein synthesis and folding in the lumen of the endoplasmic reticulum (ER), leading to increased ER stress in the cells of GBM tissues. To mitigate this stress the cancer cells have intelligently adopted a plethora of response mechanisms and Unfolded Protein Response (UPR) is one of those. To bear with this exhaustive situation cells upregulate a strong protein degradation system in form of 26S proteasome and blocking of proteasomal gene synthesis may be a potential therapeutic action against GBM. Proteasomal gene synthesis is exclusively dependent on the transcription factor Nuclear respiratory factor 1 (NRF1) and its activating enzyme DNA damage inducible 1 homolog 2 (DDI2). Here in this study, we performed molecular docking against DDI2 with the 20 FDA-approved drugs and identified Alvimopan and Levocabastine as the top two compounds with the best binding score along with the standard drug Nelfinavir. MD simulation (100 ns) of these protein-ligand docked complexes reveals that the stability and compactness of Alvimopan are high in comparison with Nelfinavir. Our in-silico (Molecular docking and Molecular dynamics simulation) studies pointed out that Alvimopan may be repurposed as a DDI2 inhibitor and can be used as a potential anticancer agent for the treatment of brain tumors.Communicated by Ramaswamy H. Sarma.
摘要：
胶质母细胞瘤,最严重的脑肿瘤和诊断后一年内死亡的主要原因，其特征是过度的蛋白质合成和内质网（ER）内腔中的折叠，导致GBM组织细胞内质网应激增加。为了减轻这种压力，癌细胞智能地采用了过多的反应机制，未折叠蛋白反应（UPR）就是其中之一。为了承受这种详尽的情况，细胞以26S蛋白酶体的形式上调了强大的蛋白质降解系统，并且阻断蛋白酶体基因合成可能是针对GBM的潜在治疗作用。蛋白酶体基因合成仅依赖于转录因子核呼吸因子1（NRF1）及其激活酶DNA损伤诱导型1同源物2（DDI2）。在这项研究中，我们使用20种FDA批准的药物对DDI2进行了分子对接,并将Alvimopan和左卡巴司汀与标准药物奈非那韦一起确定为结合评分最好的前两种化合物.这些蛋白质-配体对接复合物的MD模拟（100ns）表明，与奈非那韦相比，Alvimopan的稳定性和紧密度很高。我们的计算机（分子对接和分子动力学模拟）研究指出，Alvimopan可能被重新用作DDI2抑制剂，并可用作治疗脑肿瘤的潜在抗癌药物。由RamaswamyH.Sarma沟通。
