Molecular modeling studies of pseudouridine isoxazolidinyl nucleoside analogues as potential inhibitors of the pseudouridine 5ʹ-monophosphate glycosidase

Abstract

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.

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A series of pseudouridine isoxazolidinyl nucleoside analogues were in silico screened for their capacity to compete with pseudouridine 5ʹ-monophosphate in the occupancy of the active site of the pseudouridine 5ʹ-monophosphate glycosidase. Based on the computationally obtained results, derivative 1 5ʹ-monophosphate resulted as an ideal candidate to potential inhibit the enzyme activity also showing a weak capacity to binding to the plasma protein, only a moderate capacity to permeate the blood-brain barrier, and a non-carcinogenicity in rat and mouse.

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