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 und...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2006-11, Vol.128 (45), p.14485-14497
Main Authors: Mao, Junhong, Mukherjee, Sujoy, Zhang, Yong, Cao, Rong, Sanders, John M, Song, Yongcheng, Zhang, Yonghui, Meints, Gary A, Gao, Yi Gui, Mukkamala, Dushyant, Hudock, Michael P, Oldfield, Eric
Format: Article
Language:English
Subjects:
BASIC BIOLOGICAL SCIENCES
BONE TISSUES
Chemistry
CRYSTALLOGRAPHY
Crystallography, X-Ray - methods
Diphosphonates - chemistry
DISEASES
ENZYME INHIBITORS
ENZYMES
Exact sciences and technology
General and physical chemistry
Geranyltranstransferase - chemistry
Magnetic Resonance Spectroscopy
national synchrotron light source
NUCLEAR MAGNETIC RESONANCE
PHOSPHONATES
PHOSPHORUS COMPLEXES
SKELETON
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja061737c