Ramatenki Vishwanath, Potlapally Sarita Rajender, Dumpati Rama Krishna, Vadija Rajender, Vuruputuri Uma
a Department of Chemistry , University College of Science and.
b Department of Chemistry , Nizam College, Osmania University , Hyderabad , Telangana , India.
J Recept Signal Transduct Res. 2015;35(6):536-49. doi: 10.3109/10799893.2014.969375. Epub 2015 Sep 4.
Cancer is a major health problem in the world. The initiation and progression of cancer is due to imbalance between the programmed cell growth and death. These processes are triggered by the ubiquitin family enzymes. The ubiquitin-like proteins are responsible for the cell metabolism. Ubiquitin-dependent proteolysis by the 26s proteasome plays a crucial role in cell cycle progression as well as in tumorigenesis. In the ubiquitin proteasomal degradation pathway, ubiquitin conjugation enzyme E2A (UBE2A) binds with ubiquitin ligase RAD18, results in polyubiquitation reaction and cell cycle progression. UBE2A is an important contributing factor for the control of tumorigenesis. In the present work, the 3D model of the protein UBE2A was generated by homology modeling technique. The generated 3D structure of the UBE2A was validated, and active site was identified using standard computational protocols. The active site was subjected to structure-based virtual screening using small molecule data banks, and new molecules were identified. The ADME properties of the new ligand molecules were predicted, and the new ligands are identified as potent UBE2A antagonists for cancer therapy.
癌症是全球主要的健康问题。癌症的发生和发展是由于程序性细胞生长与死亡之间的失衡所致。这些过程由泛素家族酶触发。类泛素蛋白负责细胞代谢。26S蛋白酶体介导的泛素依赖性蛋白水解在细胞周期进程以及肿瘤发生中起着关键作用。在泛素蛋白酶体降解途径中，泛素结合酶E2A（UBE2A）与泛素连接酶RAD18结合，导致多聚泛素化反应和细胞周期进程。UBE2A是控制肿瘤发生的一个重要因素。在本研究中，通过同源建模技术生成了蛋白质UBE2A的三维模型。对生成的UBE2A三维结构进行了验证，并使用标准计算方案鉴定了活性位点。利用小分子数据库对活性位点进行基于结构的虚拟筛选，鉴定出了新的分子。预测了新配体分子的ADME性质，并将新配体鉴定为用于癌症治疗的有效UBE2A拮抗剂。
