Solid-state NMR, crystallographic, and computational investigation of Bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes
Solid-state NMR, crystallographic, and computational investigation of Bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes
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DOI：
10.1021/ja061737c
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发表时间：
2006-11-15
影响因子：
15
通讯作者：
Oldfield, Eric
中科院分区：
文献类型：
--
作者：
Mao, Junhong;Mukherjee, Sujoy;Oldfield, Eric
双膦酸盐是一类广泛用于治疗骨吸收疾病的分子，也是免疫调节剂和抗感染剂。它们通过抑制法呢基二磷酸合酶（FPPS）发挥作用，但这些分子如何结合的细节尚未完全了解。在这里，我们报告的结果固态C-13，N-15，和P-31魔角样品旋转（MAS）NMR和量子化学调查的几个双膦酸盐，无论是作为纯化合物和绑定到FPPS时，提供有关侧链和膦酸骨架质子化状态的信息时，绑定到酶。然后，我们使用计算对接方法（通过NMR分配的电荷）来预测几种双膦酸盐如何与FPPS结合。最后，我们使用X射线晶体学来确定两个有效的双膦酸盐抑制剂的结构，发现与计算结果很好的一致性，开辟了使用NMR，量子化学和分子对接的组合，以促进其他，新的异戊二烯转移酶抑制剂的设计的可能性。
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 C-13, N-15, and P-31 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.