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
Department of Chemistry and Biophysics, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
J Am Chem Soc. 2006 Nov 15;128(45):14485-97. doi: 10.1021/ja061737c.
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.
双膦酸盐是一类广泛用于治疗骨吸收疾病的分子，同时作为免疫调节剂和抗感染药物也备受关注。它们通过抑制法尼基二磷酸合酶（FPPS）发挥作用，但这些分子的结合细节尚未完全清楚。在此，我们报告了对几种双膦酸盐进行固态（13）C、（15）N和（31）P魔角样品旋转（MAS）核磁共振及量子化学研究的结果，这些双膦酸盐既作为纯化合物，也在与FPPS结合时进行研究，以提供有关与酶结合时侧链和膦酸酯主链质子化状态的信息。然后，我们使用计算对接方法（利用核磁共振确定的电荷）来预测几种双膦酸盐与FPPS的结合方式。最后，我们利用X射线晶体学确定了两种强效双膦酸盐抑制剂的结构，发现与计算结果吻合良好，这为利用核磁共振、量子化学和分子对接相结合的方法来促进其他新型异戊二烯转移酶抑制剂的设计开辟了可能性。
