2i19 › Citations

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

Mao J, Mukherjee S, Zhang Y, Cao R, Sanders JM, Song Y, Zhang Y, Meints GA, Gao YG, Mukkamala D, Hudock MP, Oldfield E
J Am Chem Soc 128 14485-97 (2006)
Cited: 41 times
EuropePMC logo PMID: 17090032

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.

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  1. The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations. Ogungbe IV, Setzer WN. Molecules 21 E1389 (2016)

Articles - 2i19 mentioned but not cited (2)

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  6. Targeting prenylation inhibition through the mevalonate pathway. Manaswiyoungkul P, de Araujo ED, Gunning PT. RSC Med Chem 11 51-71 (2020)

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  17. Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: a QSAR investigation. Song Y, Chan JM, Tovian Z, Secrest A, Nagy E, Krysiak K, Bergan K, Parniak MA, Oldfield E. Bioorg Med Chem 16 8959-8967 (2008)
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  19. NMR hyperfine shifts in blue copper proteins: a quantum chemical investigation. Zhang Y, Oldfield E. J Am Chem Soc 130 3814-3823 (2008)
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  26. Low-energy conformers of pamidronate and their intramolecular hydrogen bonds: a DFT and QTAIM study. Arabieh M, Karimi-Jafari MH, Ghannadi-Maragheh M. J Mol Model 19 427-438 (2013)
  27. Specificity of the zinc(II), magnesium(II) and calcium(II) complexation by (pyridin-2-yl)aminomethane-1,1-diphosphonic acids and related 1,3-(thiazol-2-yl) and 1,3-(benzothiazol-2-yl) derivatives. Matczak-Jon E, Kowalik-Jankowska T, Slepokura K, Kafarski P, Rajewska A. Dalton Trans 39 1207-1221 (2010)
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  29. Toward Relatively General and Accurate Quantum Chemical Predictions of Solid-State (17)O NMR Chemical Shifts in Various Biologically Relevant Oxygen-Containing Compounds. Rorick A, Michael MA, Yang L, Zhang Y. J Phys Chem B 119 11618-11625 (2015)
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