Discovery of Inhibitors of Lupin Diadenosine 5′,5′′′-P1,P4-Tetraphosphate Hydrolase by Virtual Screening

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• 作者：Kim M. Branson ; Haydyn D. T. Mertens ; James D. Swarbrick ; Jamie I. Fletcher ; Lukasz Kedzierski ; Kenwyn R. Gayler ; Paul R. Gooley ; Brian J. Smith
• 刊名：Biochemistry
• 出版年：2009
• 出版时间：August 18, 2009
• 年：2009
• 卷：48
• 期：32
• 页码：7614-7620
• 全文大小：903K
• 年卷期：v.48,no.32(August 18, 2009)
• ISSN：1520-4995

文摘

Novel inhibitors of lupin diadenosine 5′,5′′′-P¹,P⁴-tetraphosphate (Ap₄A) 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 μM. A structural analogue of this compound also exhibited competitive inhibition with a comparable K_i of 2.9 μM. ¹H, ¹⁵N NMR spectroscopy was used to map the binding site of NSC51531 on lupin Ap₄A 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 Ap₄A hydrolase is nonspecific, suggesting that this compound may represent a useful lead in the design of specific inhibitors of the plant-like form of Ap₄A hydrolases.