Solid-State NMR, Crystallographic, and Computational Investigation of Bisphosphonates and Farnesyl Diphosphate Synthase−Bisphosphonate Complexes

Bisphosphonates are a class of molecules in widespread use in treating bone resorption diseases
and are also of interest as immunomodulators and anti-infectives. They function by inhibiting the enzyme
farnesyl diphosphate synthase (FPPS), but the details of how these molecules bind are not fully understood.
Here, we report the results of a solid-state 13C, 15N, and 31P magic-angle sample spinning (MAS) NMR and
quantum chemical investigation of several bisphosphonates, both as pure compounds and when bound to
FPPS, to provide information about side-chain and phosphonate backbone protonation states when bound
to the enzyme. We then used computational docking methods (with the charges assigned by NMR) to
predict how several bisphosphonates bind to FPPS. Finally, we used X-ray crystallography to determine
the structures of two potent bisphosphonate inhibitors, finding good agreement with the computational
results, opening up the possibility of using the combination of NMR, quantum chemistry and molecular
docking to facilitate the design of other, novel prenytransferase inhibitors.