CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5'-Diphosphate Ribose Template.
CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5'-Diphosphate Ribose Template.
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DOI：
10.1371/journal.pone.0066247
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Potter BV
中科院分区：
文献类型：
--
作者：
Moreau C;Liu Q;Graeff R;Wagner GK;Thomas MP;Swarbrick JM;Shuto S;Lee HC;Hao Q;Potter BV
CD38是一种催化Ca2+动员第二信使环腺苷5′-二磷酸核糖（cADPR）形成和代谢的多功能酶，目前存在的抑制剂很少。合成的、不可水解的配体可以促进基于结构的抑制剂设计。利用分子对接重现了环肌苷5′-二磷酸核糖（no - cidpr）与CD38的晶体结合模式，揭示了一个可利用的口袋，并预测了与Asp-155引入额外氢键相互作用的潜力。N1-cIDPR的嘌呤C-8位置（IC50 276µM）被氨基或二氨基丁烷基团扩展，并对8个修饰的化合物进行cd38催化cADPR水解的评价。8-氨基N1-cIDPR:CD38复合物的晶体学证实了与Asp-155的预测相互作用，以及来自重新排列的Glu-146的第二个氢键，证明了改善的抑制作用（IC50 56µM）。环状adp -碳环核糖（cADPcR, IC50 129µM）与CD38复合物的结晶学表明，Glu-146氢键与配体n6 -氨基成键。8-氨基N1-cIDPR和cADPcR都结合在活性位点深处，到达催化残基Glu-226，并模拟cADPR在催化过程中的可能位置。N1-cIDPR“北部”核糖单磷酸和cADPcR碳环核糖单磷酸区域的大量重叠表明该区域对抑制剂设计至关重要，导致n1 -肌苷5 ' -单磷酸（N1-IMPs）的新化合物系列。这些小片段比母体环化合物更有效地抑制cADPR的水解，其中最好的片段显示出有效的抑制作用（IC50 = 7.6µM）。与cADPR相比，这些化合物的较低分子量和相对简单性使它们成为进一步设计抑制剂的起点。
Few inhibitors exist for CD38, a multifunctional enzyme catalyzing the formation and metabolism of the Ca2+-mobilizing second messenger cyclic adenosine 5′-diphosphoribose (cADPR). Synthetic, non-hydrolyzable ligands can facilitate structure-based inhibitor design. Molecular docking was used to reproduce the crystallographic binding mode of cyclic inosine 5′-diphosphoribose (N1-cIDPR) with CD38, revealing an exploitable pocket and predicting the potential to introduce an extra hydrogen bond interaction with Asp-155. The purine C-8 position of N1-cIDPR (IC50 276 µM) was extended with an amino or diaminobutane group and the 8-modified compounds were evaluated against CD38-catalyzed cADPR hydrolysis. Crystallography of an 8-amino N1-cIDPR:CD38 complex confirmed the predicted interaction with Asp-155, together with a second H-bond from a realigned Glu-146, rationalizing the improved inhibition (IC50 56 µM). Crystallography of a complex of cyclic ADP-carbocyclic ribose (cADPcR, IC50 129 µM) with CD38 illustrated that Glu-146 hydrogen bonds with the ligand N6-amino group. Both 8-amino N1-cIDPR and cADPcR bind deep in the active site reaching the catalytic residue Glu-226, and mimicking the likely location of cADPR during catalysis. Substantial overlap of the N1-cIDPR “northern” ribose monophosphate and the cADPcR carbocyclic ribose monophosphate regions suggests that this area is crucial for inhibitor design, leading to a new compound series of N1-inosine 5′-monophosphates (N1-IMPs). These small fragments inhibit hydrolysis of cADPR more efficiently than the parent cyclic compounds, with the best in the series demonstrating potent inhibition (IC50 = 7.6 µM). The lower molecular weight and relative simplicity of these compounds compared to cADPR make them attractive as a starting point for further inhibitor design.
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影响因子：
5.6
作者：
JONES, G;WILLETT, P;GLEN, RC
通讯作者：
GLEN, RC
影响因子：
3.5
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
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通讯作者：
Zwart PH
影响因子：
5.6
作者：
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通讯作者：
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