Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: A crystallographic and computational investigation

Cammy K.M. Chen, Michael P. Hudock, Yonghui Zhang, Rey Ting Guo, Rong Cao, Hwan No Joo, Po Huang Liang, Tzu Ping Ko, Tao Hsin Chang, Shiou Chi Chang, Yongcheng Song, Jordan Axelson, Anup Kumar, Andrew H.J. Wang, Eric Oldfield

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)

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 Mg2+ 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 Å. 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.

Original languageEnglish
Pages (from-to)5594-5607
Number of pages14
JournalJournal of Medicinal Chemistry
Volume51
Issue number18
DOIs
Publication statusPublished - Sep 25 2008
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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