Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: A potential route to new bone antiresorption and antiparasitic agents

Christina M. Szabo, Yoshihiro Matsumura, Sayaka Fukura, Michael B. Martin, John M. Sanders, Suraj Sengupta, John A. Cieslak, Timothy C. Loftus, Christopher R. Lea, Hyung Jae Lee, Ali Koohang, Robert M. Coates, Hiroshi Sagami, Eric Oldfield

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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 μM. None of the nitrogen-containing bisphosphonates that inhibit farnesyl diphosphate synthase were effective in inhibiting the GGPPSase enzyme. Using threedimensional quantitative structure-activity relationship/comparative molecular field analysis (CoMFA) methods, we find a good correlation between experimental and predicted activity: R2 = 0.938, Rcv2 = 0.900, Rbs2 = 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).

Original languageEnglish
Pages (from-to)2185-2196
Number of pages12
JournalJournal of Medicinal Chemistry
Volume45
Issue number11
DOIs
Publication statusPublished - 2002 May 23

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Szabo, C. M., Matsumura, Y., Fukura, S., Martin, M. B., Sanders, J. M., Sengupta, S., Cieslak, J. A., Loftus, T. C., Lea, C. R., Lee, H. J., Koohang, A., Coates, R. M., Sagami, H., & Oldfield, E. (2002). Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: A potential route to new bone antiresorption and antiparasitic agents. Journal of Medicinal Chemistry, 45(11), 2185-2196. https://doi.org/10.1021/jm010412y