Human farnesyl pyrophosphate synthase inhibition by nitrogen bisphosphonates: a 3D-QSAR study

J Comput Aided Mol Des. 2013 Aug;27(8):739-54. doi: 10.1007/s10822-013-9674-2. Epub 2013 Aug 24.


We report the results of a comparative molecular field analysis and comparative molecular similarity index analysis of the human farnesyl pyrophosphate synthase (FPPS) inhibition by nitrogen bisphosphonates (NBPs) taking into account their time-dependent inhibition efficacies. The 3D-QSAR models obtained provide steric, electrostatic and hydrophobic contour maps consistent with the interactions into the active site of human FPPS observed in available crystallographic structures. Furthermore, the 3D-QSAR models obtained provide accurately IC50 values of the NBPs of the training set. The predictive ability of these 3D-QSAR models was found to rely on the choice of biologically active conformations of the target molecules and on a careful examination of the protonation status of the NBPs in the training set. The best models obtained can be useful to predict biological values of a high number of NBPs that have been used for the treatment of different diseases as potential inhibitors of the activity of the FPPS enzyme.

MeSH terms

  • Diphosphonates / chemistry*
  • Diphosphonates / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Geranyltranstransferase / antagonists & inhibitors*
  • Geranyltranstransferase / metabolism
  • Humans
  • Models, Molecular
  • Nitrogen / chemistry*
  • Nitrogen / pharmacology*
  • Quantitative Structure-Activity Relationship*


  • Diphosphonates
  • Enzyme Inhibitors
  • Geranyltranstransferase
  • Nitrogen