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

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• 作者：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
• 刊名：Journal of the American Chemical Society
• 出版年：2006
• 出版时间：November 15, 2006
• 年：2006
• 卷：128
• 期：45
• 页码：14485 - 14497
• 全文大小：474K
• 年卷期：v.128,no.45(November 15, 2006)
• ISSN：1520-5126

文摘

Bisphosphonates are a class of molecules in widespread use in treating bone resorption diseasesand are also of interest as immunomodulators and anti-infectives. They function by inhibiting the enzymefarnesyl 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 andquantum chemical investigation of several bisphosphonates, both as pure compounds and when bound toFPPS, to provide information about side-chain and phosphonate backbone protonation states when boundto the enzyme. We then used computational docking methods (with the charges assigned by NMR) topredict how several bisphosphonates bind to FPPS. Finally, we used X-ray crystallography to determinethe structures of two potent bisphosphonate inhibitors, finding good agreement with the computationalresults, opening up the possibility of using the combination of NMR, quantum chemistry and moleculardocking to facilitate the design of other, novel prenytransferase inhibitors.