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Molecules 2008, 13(10), 2426-2441; doi:10.3390/molecules13102426

Discovery of a Novel CCR5 Antagonist Lead Compound Through Fragment Assembly

1, 2, 4, 1, 1, 2,* , 1,*  and 1,4
1 School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, P.R. China 2 The National Center for Drug Screening, Chinese Academy of Sciences, Shanghai 201203, P.R. China 3 School of Biotechnology, Southwest University, Chongqing 400715, P.R. China 4 Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P.R. China
* Authors to whom correspondence should be addressed.
Received: 30 September 2008 / Revised: 18 September 2008 / Accepted: 18 September 2008 / Published: 1 October 2008
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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.
Keywords: CCR5 antagonist; fragment assembly; HIV-1; molecular modeling CCR5 antagonist; fragment assembly; HIV-1; molecular modeling
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Liu, Y.; Zhou, E.; Yu, K.; Zhu, J.; Zhang, Y.; Xie, X.; Li, J.; Jiang, H. Discovery of a Novel CCR5 Antagonist Lead Compound Through Fragment Assembly. Molecules 2008, 13, 2426-2441.

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