Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents.
Article Details
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Szabo CM, Matsumura Y, Fukura S, Martin MB, Sanders JM, Sengupta S, Cieslak JA, Loftus TC, Lea CR, Lee HJ, Koohang A, Coates RM, Sagami H, Oldfield E
Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents.
J Med Chem. 2002 May 23;45(11):2185-96.
- PubMed ID
- 12014956 [ View in PubMed]
- Abstract
We report the inhibition of a human recombinant geranylgeranyl diphosphate synthase (GGPPSase) by 23 bisphosphonates and six azaprenyl diphosphates. The IC50 values range from 140 nM to 690 microM. None of the nitrogen-containing bisphosphonates that inhibit farnesyl diphosphate synthase were effective in inhibiting the GGPPSase enzyme. Using three-dimensional quantitative structure-activity relationship/comparative molecular field analysis (CoMFA) methods, we find a good correlation between experimental and predicted activity: R2 = 0.938, R(cv)2 = 0.900, R(bs)2 = 0.938, and F-test = 86.8. To test the predictive utility of the CoMFA approach, we used three training sets of 25 compounds each to generate models to predict three test sets of three compounds. The rms pIC50 error for the nine predictions was 0.39. We also investigated the pharmacophore of these GGPPSase inhibitors using the Catalyst method. The results demonstrated that Catalyst predicted the pIC50 values for the nine test set compounds with an rms error of 0.28 (R2 between experimental and predicted activity of 0.948).
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) (1-HYDROXYHEPTANE-1,1-DIYL)BIS(PHOSPHONIC ACID) Geranylgeranyl pyrophosphate synthase IC 50 (nM) 11000 N/A N/A Details Alendronic acid Farnesyl pyrophosphate synthase IC 50 (nM) 50 N/A N/A Details Ibandronate Farnesyl pyrophosphate synthase IC 50 (nM) 20 N/A N/A Details Lauryl alcohol diphosphonic acid Geranylgeranyl pyrophosphate synthase IC 50 (nM) 920 N/A N/A Details Pamidronic acid Farnesyl pyrophosphate synthase IC 50 (nM) 200 N/A N/A Details Risedronic acid Farnesyl pyrophosphate synthase IC 50 (nM) 10 N/A N/A Details