Wang Yan, Lin Huang-Quan, Wang Ping, Hu Jian-Shu, Ip Tsz-Ming, Yang Liu-Meng, Zheng Yong-Tang, Chi-Cheong Wan David
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR, China.
Shenzhen Research Institute, the Chinese University of Hong Kong , Shenzhen 518057, China.
J Chem Inf Model. 2017 Sep 25;57(9):2336-2343. doi: 10.1021/acs.jcim.7b00402. Epub 2017 Sep 11.
Protein-protein interaction between lens epithelium-derived growth factor (LEDGF/p75) and HIV-1 integrase becomes an attractive target for anti-HIV drug development. The blockade of this interaction by small molecules could potentially inhibit HIV-1 replication. These small molecules are termed as LEDGINs; and several newly identified LEDGINs have been reported to significantly reduce HIV-1 replication. Through this project, we have finished the docking screening of the Maybridge database against the p75 binding site of HIV-1 integrase using both DOCK and Autodock Vina software. Finally, we have successfully identified a novel scaffold LEDGINs inhibitor DW-D-5. Its antiviral activities and anticatalytic activity of HIV-1 integrase are similar to other LEDGINs under development. We demonstrated that the combination of DW-D-5 and FDA approved anti-HIV drugs resulted in additive inhibitory effects on HIV-1 replication, indicating that DW-D-5 could be an important component of combination pills for clinic use in HIV treatment.
晶状体上皮衍生生长因子（LEDGF/p75）与HIV-1整合酶之间的蛋白质-蛋白质相互作用成为抗HIV药物开发的一个有吸引力的靶点。小分子对这种相互作用的阻断可能会抑制HIV-1复制。这些小分子被称为LEDGINs；据报道，几种新发现的LEDGINs能显著降低HIV-1复制。通过这个项目，我们使用DOCK和Autodock Vina软件完成了针对HIV-1整合酶p75结合位点的Maybridge数据库对接筛选。最后，我们成功鉴定出一种新型骨架LEDGINs抑制剂DW-D-5。其抗病毒活性和对HIV-1整合酶催化活性的抑制作用与其他正在研发的LEDGINs相似。我们证明，DW-D-5与FDA批准的抗HIV药物联合使用对HIV-1复制产生了相加抑制作用，表明DW-D-5可能是用于HIV治疗临床的复方药丸的重要成分。
