Inhibition of Geranylgeranyl Diphosphate Synthase by Bisphosphonates: A Crystallographic and Computational Investigation
Resource
Journal of medicinal chemistry 51 (18): 5594-5607
Journal
Journal of Medicinal Chemistry
Pages
5594-5607
Date Issued
2008
Date
2008
Author(s)
Chen, Cammy K.-M.
Hudock, Michael P.
Zhang, Yonghui
Guo, Rey-Ting
Cao, Rong
No, Joo Hwan
Liang, Po-Huang
Ko, Tzu-Ping
Chang, Tao-Hsin
Chang, Shiou-chi
Song, Yongcheng
Axelson, Jordan
Kumar, Anup
Wang, Andrew H.-J.
Oldfield, Eric
Abstract
We report the X-ray structures of several bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, a target for anticancer drugs. Bisphosphonates containing unbranched side chains bind to either the farnesyl diphosphate (FPP) substrate site, the geranylgeranyl diphosphate (GGPP) product site, and in one case, both sites, with the bisphosphonate moiety interacting with 3 Mg (2+) that occupy the same position as found in FPP synthase. However, each of three "V-shaped" bisphosphonates bind to both the FPP and GGPP sites. Using the Glide program, we reproduced the binding modes of 10 bisphosphonates with an rms error of 1.3 A. Activities of the bisphosphonates in GGPPS inhibition were predicted with an overall error of 2x by using a comparative molecular similarity analysis based on a docked-structure alignment. These results show that some GGPPS inhibitors can occupy both substrate and product site and that binding modes as well as activity can be accurately predicted, facilitating the further development of GGPPS inhibitors as anticancer agents.
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