title: Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes.
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 (13)C, (15)N, and (31)P 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.
authors.affiliation: Department of Chemistry and Biophysics, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Junhong
authors.initials: J
authors.lastname: Mao
authors.forename: Sujoy
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Cao
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gary A
authors.initials: GA
authors.lastname: Meints
authors.forename: Yi Gui
authors.initials: YG
authors.lastname: Gao
authors.forename: Dushyant
authors.initials: D
authors.lastname: Mukkamala
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hudock
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D018360:Crystallography, X-Ray / Q000379:methods*; D004164:Diphosphonates / Q000737:chemistry*; D051228:Geranyltranstransferase / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy
chemical_list: D004164:Diphosphonates; D051228:Geranyltranstransferase