3 years ago

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

Molecular modeling studies of pseudouridine isoxazolidinyl nucleoside analogues as potential inhibitors of the pseudouridine 5ʹ-monophosphate glycosidase
Maria Dichiara, Emanuele Amata, Arcangelo Damigella, Orazio Prezzavento, Venerando Pistarà, Giuseppe Floresta, Francesco Punzo, Antonio Rescifina, Agostino Marrazzo
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. This article is protected by copyright. All rights reserved. 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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13113

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