Atatreh Noor, Ghattas Mohammad A, Bardaweel Sanaa K, Rawashdeh Sara Al, Sorkhy Mohammad Al
Department of Pharmaceutical Sciences, College of Pharmacy, Al Ain University of Science and Technology, Al Ain, Abu Dhabi, United Arab Emirates,
Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan.
Drug Des Devel Ther. 2018 Nov 2;12:3741-3752. doi: 10.2147/DDDT.S182444. eCollection 2018.
The tumor suppressor protein p53 plays an important role in preventing tumor formation and progression through its involvement in cell division control and initiation of apoptosis. Mdm2 protein controls the activity of p53 protein through working as ubiquitin E3 ligase promoting p53 degradation through the proteasome degradation pathway. Inhibitors for Mdm2-p53 interaction have restored the activity of p53 protein and induced cancer fighting properties in the cell.
The objective of this study is to use computer-aided drug discovery techniques to search for new Mdm2-p53 interaction inhibitors.
A set of pharmacophoric features were created based on a standard Mdm2 inhibitor and this was used to screen a commercial drug-like ligand library; then potential inhibitors were docked and ranked in a multi-step protocol using GLIDE. Top ranked ligands from docking were evaluated for their inhibition activity of Mdm2-p53 interaction using ELISA testing.
Several compounds showed inhibition activity at the submicromolar level, which is comparable to the standard inhibitor Nutlin-3a. Furthermore, the discovered inhibitors were evaluated for their anticancer activities against different breast cancer cell lines, and they showed an interesting inhibition pattern.
The reported inhibitors can represent a starting point for further SAR studies in the future and can help in the discovery of new anticancer agents.
肿瘤抑制蛋白p53通过参与细胞分裂控制和启动细胞凋亡，在预防肿瘤形成和进展中发挥重要作用。Mdm2蛋白作为泛素E3连接酶，通过蛋白酶体降解途径促进p53降解，从而控制p53蛋白的活性。Mdm2-p53相互作用的抑制剂可恢复p53蛋白的活性，并在细胞中诱导抗癌特性。
本研究的目的是使用计算机辅助药物发现技术寻找新的Mdm2-p53相互作用抑制剂。
基于一种标准的Mdm2抑制剂创建了一组药效团特征，并用于筛选商业类药物配体库；然后使用GLIDE在多步骤方案中对接潜在抑制剂并进行排名。对接中排名靠前的配体使用ELISA测试评估其对Mdm2-p53相互作用的抑制活性。
几种化合物在亚微摩尔水平显示出抑制活性，这与标准抑制剂Nutlin-3a相当。此外，对发现的抑制剂针对不同乳腺癌细胞系的抗癌活性进行了评估，它们显示出有趣的抑制模式。
所报道的抑制剂可作为未来进一步进行构效关系研究的起点，并有助于发现新的抗癌药物。
