Journal
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Volume 27, Issue 8, Pages 739-754Publisher
SPRINGER
DOI: 10.1007/s10822-013-9674-2
Keywords
Bisphosphonates; 3D-QSAR; Human farnesyl pyrophosphate synthase; Inhibitors
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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.
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