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

• Published in: Chemical biology & drug design 2018-02, Vol.91 (2), p.519-525
• Main Authors: Floresta, Giuseppe, Pistarà, Venerando, Amata, Emanuele, Dichiara, Maria, Damigella, Arcangelo, Marrazzo, Agostino, Prezzavento, Orazio, Punzo, Francesco, Rescifina, Antonio
• Format: Article
• Language: English
• Subjects: ADME‐Tox; Binding Sites; Blood-Brain Barrier - metabolism; Catalytic Domain; Glycoside Hydrolases - antagonists & inhibitors; Glycoside Hydrolases - metabolism; Hydrogen Bonding; in silico profiling; Isoxazoles - chemistry; isoxazolidinyl nucleoside analogues; Molecular Docking Simulation; Nucleosides - analogs & derivatives; Nucleosides - metabolism; pseudouridine; Pseudouridine - chemistry; pseudouridine 5ʹ‐monophosphate glycosidase; Thermodynamics
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13113

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. 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.