Liu Yanqing, Zhou Enkun, Yu Kunqian, Zhu Jin, Zhang Yu, Xie Xin, Li Jian, Jiang Hualiang
School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, PR China.
Molecules. 2008 Oct 1;13(10):2426-41. doi: 10.3390/molecules13102426.
CCR5, as the major co-receptor for HIV-1 entry, is an attractive novel target for the pharmaceutical industry in the HIV-1 therapeutic area. In this study, based on the structures of maraviroc and 1,4-bis(4-(7-chloroquinolin-4-yl)piperazin-1-yl)butane-1,4-dione (1), which was identified using structure-based virtual screening in conjunction with a calcium mobilization assay, a series of novel small molecule CCR5 antagonists have been designed and synthesized through fragment assembly. Preliminary SARs were obtained, which are in good agreement with the molecular binding model and should prove helpful for future antagonist design. The novel scaffold presented here might also be useful in the development of maraviroc-derived second generation CCR5 antagonists.
CCR5作为HIV-1进入细胞的主要共受体，是制药行业在HIV-1治疗领域极具吸引力的新型靶点。在本研究中，基于马拉维若和1,4-双(4-(7-氯喹啉-4-基)哌嗪-1-基)丁烷-1,4-二酮(1)的结构（1是通过基于结构的虚拟筛选结合钙动员试验鉴定得到的），通过片段组装设计并合成了一系列新型小分子CCR5拮抗剂。获得了初步的构效关系，与分子结合模型高度吻合，应为未来拮抗剂的设计提供帮助。此处展示的新型骨架在马拉维若衍生的第二代CCR5拮抗剂的开发中可能也有用处。
