Premium
Molecular modeling studies of pseudouridine isoxazolidinyl nucleoside analogues as potential inhibitors of the pseudouridine 5ʹ‐monophosphate glycosidase
Author(s) -
Floresta Giuseppe,
Pistarà Venerando,
Amata Emanuele,
Dichiara Maria,
Damigella Arcangelo,
Marrazzo Agostino,
Prezzavento Orazio,
Punzo Francesco,
Rescifina Antonio
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13113
Subject(s) - pseudouridine , chemistry , biochemistry , enzyme , nucleoside , stereochemistry , lyase , inosine , uridine , rna , gene
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.