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Computational investigation of FDA approved drugs as selective PARP-1 inhibitors by targeting BRCT domain for cancer therapy
Journal of Molecular Graphics and Modelling ( IF 2.9 ) Pub Date : 2021-04-06 , DOI: 10.1016/j.jmgm.2021.107919
Chandan Kumar 1 , P T V Lakshmi 1 , Annamalai Arunachalam 2
Affiliation  

Poly(ADP-ribose) polymerase-1 is a promising target for the treatment of cancer due to its involvement in base excision repair pathways for repairing DNA single-strand breaks. However, available PARP-1 inhibitors target a highly conserved PARPs catalytic domain, which causes toxicity due to the off-target activity. Therefore, the present study was hypothesized to identify selective inhibitors by targeting specific protein-protein interacting (PPI) PARP-1 BRCT domain. Moreover, PPI hotspot residues (Gly399, Lys400, Leu401, Lys441 & Lys442) and a druggable pocket was detected to screen small molecule inhibitors. Hence, two FDA approved drug molecules (levoleucovorin and balsalazide) were recognized to fit in the druggable pocket. Since they are already under investigation for anti-cancer activity, thus could be further explored in PARP-1 sensitive cancer cells to expand their selectivity and develop as effective anti-cancer agents. Besides, the study also provides detailed structural insight of PARP-1 and XRCC1 complex through their BRCT domains.



中文翻译:

通过靶向 BRCT 域进行癌症治疗的 FDA 批准药物作为选择性 PARP-1 抑制剂的计算研究

聚(ADP-核糖)聚合酶-1 是治疗癌症的有希望的靶点,因为它参与修复 DNA 单链断裂的碱基切除修复途径。然而,可用的 PARP-1 抑制剂靶向高度保守的 PARPs 催化结构域,由于脱靶活性而导致毒性。因此,本研究假设通过靶向特定蛋白质-蛋白质相互作用 (PPI) PARP-1 BRCT 域来鉴定选择性抑制剂。此外,检测到 PPI 热点残基(Gly399、Lys400、Leu401、Lys441 和 Lys442)和可成药口袋以筛选小分子抑制剂。因此,两种 FDA 批准的药物分子(左旋叶酸和巴柳氮)被认为适合药物袋。由于他们已经在研究抗癌活性,因此可以在 PARP-1 敏感的癌细胞中进一步探索,以扩大其选择性并开发为有效的抗癌剂。此外,该研究还通过其 BRCT 域提供了 PARP-1 和 XRCC1 复合物的详细结构见解。

更新日期:2021-04-06
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