2-Hexylthio-尾,纬-CH2-ATP is an Effective and Selective NTPDase2 Inhibitor

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• 作者：Irina Gillerman ; Joanna Lecka ; Luba Simhaev ; Mercedes N. Munkonda ; Michel Fausther ; Mireia Mart铆n-Satu茅 ; Hanoch Senderowitz ; Jean S茅vigny ; Bilha Fischer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：5919-5934
• 全文大小：962K
• ISSN：1520-4804

文摘

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-尾,纬-methylene-ATP, 2. Analogue 2 was stable to hydrolysis by NTPDase1, -2, -3, and -8. It inhibited hNTPDase2 with K_i 20 渭M, while only marginally (5鈥?5%) 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.