Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes

Junhong Mao, Sujoy Mukherjee, Yong Zhang, Rong Cao, John M. Sanders, Yongcheng Song, Yonghui Zhang, Gary A. Meints, Yi Gui Gao, Dushyant Mukkamala, Michael P. Hudock, Eric Oldfield

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)14485-14497
Number of pages13
JournalJournal of the American Chemical Society
Volume128
Issue number45
DOIs
StatePublished - Nov 15 2006

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry

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