Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: A potential route to new bone antiresorption and antiparasitic agents
Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: A potential route to new bone antiresorption and antiparasitic agents
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DOI：
10.1021/jm010412y
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发表时间：
2002-05-23
影响因子：
7.3
通讯作者：
Oldfield, E
中科院分区：
文献类型：
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作者：
Szabo, CM;Matsumura, Y;Oldfield, E
我们报告了23种二磷酸盐和6种氮杂异戊二烯二磷酸盐对人重组香叶基香叶基二磷酸合酶（GGPPSase）的抑制作用。IC 50值范围为140 nM至690 μ M。抑制法呢基二磷酸合酶的含氮二膦酸盐均不能有效抑制GGPPSase酶。使用三维定量结构-活性关系/比较分子场分析（CoMFA）方法，我们发现实验和预测活性之间具有良好的相关性：R-2 = 0.938，R-cv（2）= 0.900，R-bs（2）= 0.938，F-检验= 86.8。为了测试CoMFA方法的预测效用，我们使用了三个训练集，每个训练集有25种化合物，以生成模型来预测三个测试集的三种化合物。9次预测的rms pIC（50）误差为0.39。我们还使用催化剂方法研究了这些GGPPSase抑制剂的药效团。结果表明，Catalyst预测了9种测试集化合物的pIC（50）值，均方根误差为0.28（实验和预测活性之间的R-2为0.948）。
We report the inhibition of a human recombinant geranylgeranyl diphosphate synthase (GGPPSase) by 23 bisphosphonates and six azaprenyl diphosphates. The IC50 values range from 140 nM to 690,muM. None of the nitrogen-containing bisphosphonates that inhibit farnesyl diphosphate synthase were effective in inhibiting the GGPPSase enzyme. Using three-dimensional quantitative structure-activity relationship/comparative molecular field analysis (CoMFA) methods, we find a good correlation between experimental and predicted activity: R-2 = 0.938, R-cv(2) = 0.900, R-bs(2) = 0.938, and F-test = 86.8. To test the predictive utility of the CoMFA approach, we used three training sets of 25 compounds each to generate models to predict three test sets of three compounds. The rms pIC(50) error for the nine predictions was 0.39. We also investigated the pharmacophore of these GGPPSase inhibitors using the Catalyst method. The results demonstrated that Catalyst predicted the pIC(50) values for the nine test set compounds with an rms error of 0.28 (R-2 between experimental and predicted activity of 0.948).