title: Discovery of a novel CCR5 antagonist lead compound through fragment assembly.
abstract: 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.
authors.affiliation: School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, PR China. yanqing_liu@163.com
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Enkun
authors.initials: E
authors.lastname: Zhou
authors.forename: Kunqian
authors.initials: K
authors.lastname: Yu
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002074:Butanones / Q000138:chemical synthesis* / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D020013:Calcium Signaling / Q000187:drug effects; D003510:Cyclohexanes; D015195:Drug Design; D006801:Humans; D000077592:Maraviroc; D013329:Structure-Activity Relationship; D014230:Triazoles
chemical_list: D019380:Anti-HIV Agents; D002074:Butanones; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc