Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design

被引:72
作者
Tsao, Desiree H. H. [1 ]
Sutherland, Alan G.
Jennings, Lee. D.
Li, Yuanhong
Rush, Thomas S., III
Alvarez, Juan C.
Ding, Weidong
Dushin, Elizabeth G.
Dushin, Russell G.
Haney, Steve A.
Kenny, Cynthia H.
Malakian, A. Karl
Nilakantan, Ramaswamy
Mosyak, Lidia
机构
[1] Wyeth Res, Struct Biol & Computat Chem, Cambridge, MA 02140 USA
[2] Wyeth Res, Biophys Enzymol, Pearl River, NY 10965 USA
[3] Wyeth Res, Med Chem, Pearl River, NY 10965 USA
[4] Wyeth Res, Biol Technol, Cambridge, MA 02140 USA
关键词
D O I
10.1016/j.bmc.2006.07.050
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
ZipA is a membrane anchored protein in Escherichia coli that interacts with FtsZ, a homolog of eukaryotic tubulins, forming a septal ring structure that mediates bacterial cell division. Thus, the ZipA/FtsZ protein-protein interaction is a potential target for an antibacterial agent. We report here an NMR-based fragment screening approach which identified several hits that bind to the C-terminal region of ZipA. The screen was performed by H-1-N-15 HSQC experiments on a library of 825 fragments that are small, lead-like, and highly soluble. Seven hits were identified, and the binding mode of the best one was revealed in the X-ray crystal structure. Similar to the ZipA/FtsZ contacts, the driving force in the binding of the small molecule ligands to ZipA is achieved through hydrophobic interactions. Analogs of this hit were also evaluated by NMR and X-ray crystal structures of these analogs with ZipA were obtained, providing structural information to help guide the medicinal chemistry efforts. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码:7953 / 7961
页数:9
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