Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
Eur J Med Chem. 2013 Oct;68:405-11. doi: 10.1016/j.ejmech.2013.07.025. Epub 2013 Aug 9.
The disruption of crucial interactions between HIV-1 Integrase and cellular cofactor LEDGF/p75 represents an emerging approach for the design and development of new antiretroviral agents. In this study we report the successful application of a structure-based virtual screening strategy for the discovery of natural hit structures able to inhibit Integrase-LEDGF/p75 interaction. The application of sequential filters (drug-likeness, 3D-pharmacophore mapping, docking, molecular dynamics simulations) yielded a hit list of compounds, out of which 9 were tested in the in vitro AlphaScreen assays and 8 exhibited a detectable inhibition of the interaction between the two proteins. The best inhibitors belong to different chemical classes and could be represent a good starting point for further optimization and structure-activity relationship studies.
HIV-1 整合酶与细胞辅助因子 LEDGF/p75 之间关键相互作用的破坏代表了设计和开发新型抗逆转录病毒药物的一种新出现的方法。在这项研究中，我们报告了成功应用基于结构的虚拟筛选策略来发现能够抑制整合酶-LEDGF/p75 相互作用的天然命中结构的情况。连续过滤器（药物相似性、3D 药效团映射、对接、分子动力学模拟）的应用产生了一个命中化合物列表，其中 9 种在体外 AlphaScreen 测定中进行了测试，8 种显示出两种蛋白质之间相互作用的可检测抑制作用。最好的抑制剂属于不同的化学类别，可以作为进一步优化和构效关系研究的良好起点。
