Department of Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
J Med Chem. 2014 Jul 24;57(14):5919-34. doi: 10.1021/jm401933c. Epub 2014 Jul 14.
NTPDase2 catabolizes nucleoside triphosphates and consequently, through the interaction of nucleotides with P2 receptors, controls multiple biological responses. NTPDase2 inhibitors could modulate responses induced by nucleotides in thrombosis, inflammation, cancer, etc. Here we developed a set of ATP analogues as potential NTPDase inhibitors and identified a subtype-selective and potent NTPDase2 inhibitor, 2-hexylthio-β,γ-methylene-ATP, 2. Analogue 2 was stable to hydrolysis by NTPDase1, -2, -3, and -8. It inhibited hNTPDase2 with Ki 20 μM, while only marginally (5-15%) inhibiting NTPDase1, -3, and -8. Homology models of hNTPDase1 and -2 were constructed. Docking and subsequent linear interaction energy (LIE) simulations provided a correlation with r2=0.94 between calculated and experimental inhibition data for the triphosphate analogues considered in this work. The origin of selectivity of 2 for NTPDase2 over NTPDase1 is the thiohexyl moiety of 2 which is favorably located within a hydrophobic pocket, whereas in NTPDase1 it is exposed to the solvent.
NTPDase2 分解核苷三磷酸，因此通过核苷酸与 P2 受体的相互作用，控制多种生物反应。NTPDase2 抑制剂可以调节血栓形成、炎症、癌症等过程中核苷酸诱导的反应。在这里，我们开发了一系列 ATP 类似物作为潜在的 NTPDase 抑制剂，并鉴定出一种亚型选择性和有效的 NTPDase2 抑制剂，2-己基硫代-β，γ-亚甲基-ATP（2）。类似物 2 对 NTPDase1、-2、-3 和 -8 的水解稳定。它以 Ki 20 μM 抑制 hNTPDase2，而对 NTPDase1、-3 和 -8 的抑制作用仅略有（5-15%）。构建了 hNTPDase1 和 -2 的同源模型。对接和随后的线性相互作用能（LIE）模拟提供了与本工作中考虑的三磷酸类似物的计算和实验抑制数据之间的 r2=0.94 的相关性。2 对 NTPDase2 的选择性优于 NTPDase1 的原因是 2 的硫己基部分有利于位于疏水口袋内，而在 NTPDase1 中它暴露于溶剂中。
