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

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K-M Chen C, Hudock MP, Zhang Y, Guo RT, Cao R, No JH, Liang PH, Ko TP, Chang TH, Chang SC, Song Y, Axelson J, Kumar A, Wang AH, Oldfield E

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

J Med Chem. 2008 Sep 25;51(18):5594-607. doi: 10.1021/jm800325y.

PubMed ID
18800762 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(1-HYDROXYHEPTANE-1,1-DIYL)BIS(PHOSPHONIC ACID)Geranylgeranyl pyrophosphate synthaseIC 50 (nM)11220737Details
(1-HYDROXYNONANE-1,1-DIYL)BIS(PHOSPHONIC ACID)Geranylgeranyl pyrophosphate synthaseIC 50 (nM)710737Details
(2,2-DIPHOSPHONOETHYL)(DODECYL)DIMETHYLPHOSPHONIUMGeranylgeranyl pyrophosphate synthaseIC 50 (nM)100737Details
(6E,11E)-HEPTADECA-6,11-DIENE-9,9-DIYLBIS(PHOSPHONIC ACID)Geranylgeranyl pyrophosphate synthaseIC 50 (nM)1860737Details
[2-(3-DIBENZOFURAN-4-YL-PHENYL)-1-HYDROXY-1-PHOSPHONO-ETHYL]-PHOSPHONIC ACIDGeranylgeranyl pyrophosphate synthaseIC 50 (nM)3980737Details
Lauryl alcohol diphosphonic acidGeranylgeranyl pyrophosphate synthaseIC 50 (nM)2690737Details
Zoledronic acidGeranylgeranyl pyrophosphate synthaseIC 50 (nM)100000737Details