Discovery of Inhibitors of Lupin Diadenosine 5′,5′"-P1,P4-Tetraphosphate Hydrolase by Virtual Screening
Discovery of Inhibitors of Lupin Diadenosine 5′,5′"-P1,P4-Tetraphosphate Hydrolase by Virtual Screening
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DOI：
10.1021/bi900813x
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发表时间：
2009-08-18
期刊：
影响因子：
2.9
通讯作者：
Smith, Brian J.
中科院分区：
文献类型：
--
作者：
Branson, Kim M.;Mertens, Haydyn D. T.;Smith, Brian J.
通过对大型虚拟化学库进行计算机筛选，已鉴定出羽扇豆二腺苷 5',5'"-P-1,P-4-四磷酸 (Ap(4)A) 水解酶的新型抑制剂。根据六种评分功能的共识对化合物进行排名。从排名前 100 的化合物中选择了 6 种，并使用单浓度等温滴定量热法初步筛选了抑制活性。其中两种化合物表现出优异的抑制活性进一步分析了溶解度特性，但只有一种 [NSC51531; 2-((8-羟基-4-(4-甲基-2-磺基苯胺基)-9,10-二氧代-9,10-二氢-1-蒽基)氨基)5-甲基苯磺酸]表现出竞争性抑制，K-i 为 1 μM。该化合物的结构类似物也表现出竞争性抑制，K-i 为 1 μM。使用 2.9 mu M. H-1、N-15 NMR 光谱绘制了 NSC51531 在羽扇豆 Ap(4)A 水解酶上的结合位点，并证明该化合物在底物结合位点上特异性结合，这与 NSC51531 与人型 Ap(4)A 水解酶的竞争性抑制结果一致，表明该化合物可能在设计类植物形式的 Ap(4)A 水解酶的特异性抑制剂方面具有重要作用。 Ap(4)A 水解酶。
Novel inhibitors of lupin diadenosine 5',5'"-P-1,P-4-tetraphosphate (Ap(4)A) hydrolase have been identified by in silico screening of a large virtual chemical library. Compounds were ranked on the basis of a consensus from six scoring functions. From the top 100 ranked compounds six were selected and initially screened for inhibitory activity using a single concentration isothermal titration calorimetry assay. Two of these compounds that showed excellent Solubility properties were further analyzed, but only one [NSC51531; 2-((8-hydroxy-4-(4-methyl-2-sulfoanilino)-9,10-dioxo-9,10-dihydro-1-anthracenyl)amino)5-methylbenzenesulfonic acid] exhibited competitive inhibition with a K-i of 1 mu M. A Structural analogue of this compound also exhibited competitive inhibition with a comparable K-i of 2.9 mu M. H-1, N-15 NMR spectroscopy was used to map the binding site of NSC51531 on lupin Ap(4)A hydrolase and demonstrated that the compound bound specifically in the substrate-binding site, consistent with the competitive inhibition results. Binding of NSC51531 to the human form of Ap(4)A hydrolase is nonspecific, suggesting that this compound may represent a useful lead in the design of specific inhibitors of the plant-like form of Ap(4)A hydrolases.