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.

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Amyloid beta (Aβ) deposits are implicated in the pathogenesis of debilitating neurodegenerative disorders such as Alzheimer’s disease. In the present study, the interactions of carbon-based nanoparticles (NPs) such as fullerene and fullerenol having different surface chemistry with Aβ were investigated using molecular dynamics simulations and docking studies. A detailed analysis of docking results showed that in 68% of the Aβ conformations, fullerene and fullerenol showed interactions with the N-terminal region of the peptide. However, the high-affinity binding site (E=−48.31 kJ/mol) of fullerene resides in the hydrophobic middle region of the peptide, whereas fullerenol interacts favorably with the charged N-terminal region with a binding energy of −50.42 kJ/mol. The above differences in binding could be attributed to the surface chemistry of fullerene and fullerenol. Moreover, the N-terminal and middle regions of Aβ play an important role in Aβ aggregation. Therefore, the binding of fullerene and fullerenol could inhibit amyloid aggregation. This information will be helpful in designing NPs for targeting amyloid-related disorders.