In this paper, we investigated the hypothesis that pseudouridine isoxazolidinyl nucleoside analogues could act as potential inhibitors of the pseudouridine 5ʹ‐monophosphate glycosidase. This purpose was pursued using molecular modeling and in silico ADME‐Tox profiling. From these studies emerged that the isoxazolidinyl derivative 1 5ʹ‐monophosphate can be effectively accommodated within the active site of the enzyme with a ligand efficiency higher than that of the natural substrate. In this context, the poor nucleofugality of the N‐protonated isoxazolidine prevents or slows down, the first mechanistic step proposed for the degradation of the pseudouridine 5ʹ‐monophosphate glycosidase, leading to the enzyme inhibition. Finally, the results of the physicochemical and ADME‐Tox informative analysis pointed out that compound 1 is weakly bounded to plasma protein, only moderately permeate the blood–brain barrier, and is non‐carcinogen in rat and mouse. To the best of our knowledge, this is the first paper that introduces the possibility of inhibition of pseudouridine 5ʹ‐monophosphate glycosidase by a molecule that competing with the natural substrate hinders the glycosidic C–C bond cleavage.

中文翻译：

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拟尿苷异恶唑啉基核苷类似物作为拟尿苷5′-单磷酸糖苷酶潜在抑制剂的分子模型研究

在本文中，我们研究了假尿苷异恶唑啉基核苷类似物可作为假尿苷5′-单磷酸糖苷酶潜在抑制剂的假说。使用分子建模和计算机模拟ADME-Tox轮廓图可以达到此目的。这些研究表明，异恶唑烷基衍生物1 5′-单磷酸可以有效地容纳在酶的活性位点，其配体效率要高于天然底物。在这种情况下，N的核易性差质子化的异恶唑烷可预防或减慢其速度，这是拟议的伪尿苷5′-单磷酸糖苷酶降解的第一步，从而导致了该酶的抑制。最后，理化和ADME-Tox信息分析的结果指出，化合物1与血浆蛋白结合较弱，仅适度渗透血脑屏障，在大鼠和小鼠中均为非致癌物。据我们所知，这是第一篇介绍与自然底物竞争阻碍糖苷碳键断裂的分子抑制拟尿苷5′-单磷酸糖苷酶的可能性的论文。