Abstract
Phosphonates and bisphosphonates have proven their pharmacological utility as inhibitors of enzymes that metabolize phosphate and pyrophosphate substrates. The blockbuster class of drugs nitrogen-containing bisphosphonates represent one of the best-known examples. Widely used to treat bone-resorption disorders, these drugs work by inhibiting the enzyme farnesyl pyrophosphate synthase. Playing a key role in the isoprenoid biosynthetic pathway, this enzyme is also a potential anticancer target. Here, we provide a comprehensive overview of the research efforts to identify new inhibitors of farnesyl pyrophosphate synthase for various therapeutic applications. While the majority of these efforts have been directed against the human enzyme, some have been targeted on its homologs from other organisms, such as protozoan parasites and insects. Our particular focus is on the structures of the target enzymes and how the structural information has guided the drug discovery efforts.
Highlights
Phosphonates and bisphosphonates are chemically stable analogs of phosphates and pyrophosphates
The findings of this study suggest that while the presence of a phosphonate group alone does not indicate bone binding for allosteric farnesyl pyrophosphate synthase (FPPS) inhibitors, bone affinity can be introduced to these compounds by adding a flexible linker together with the phosphonate group
The story of FPPS is a testimonial to this drug discovery paradigm shift
Summary
Phosphonates and bisphosphonates are chemically stable analogs of phosphates and pyrophosphates. Coordinated between the aspartic acid residues of the DDXXD motifs and the pyrophosphate moiety of the bound substrate, three Mg2+ ions mediate the electrostatic interactions between these negatively charged groups (Figure 3B). The key feature in the binding of these inhibitors is that their bulky lipophilic side chains can fully occupy the allylic substrate site hydrophobic cavity (Figures 5B,C).
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