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Nucleoside Hydrolase (nucleoside + hydrolase)

Distribution by Scientific Domains
Chemistry100%

Selected Abstracts

Quantum chemical study of leaving group activation in T. vivax nucleoside hydrolase

INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 3 2006
Stefan Loverix
Abstract General acid catalysis is a powerful and widely used strategy in enzymatic nucleophilic displacement reactions. However, in the nucleoside hydrolase of the parasite Trypanosoma vivax, crystallographic and mutagenesis studies failed to identify a general acid. The only groups in the vicinity of the leaving group that contribute to catalysis are (i) the indole side chain of Trp260, and (ii) the 5,-group of the substrate's ribose moiety. The x-ray structure of the slow Asp10Ala mutant of nucleoside hydrolase with the substrate inosine bound in the active site displays a face-to-face aromatic stacking interaction between Trp260 and the purine base of the substrate, as well as a peculiar C4,-endo ribose pucker that allows the 5,-OH group to accept an intramolecular hydrogen bond from the C8 of the purine. The first interaction (aromatic stacking) has been shown to raise the pKa of the leaving purine. Here, we present a DFT study showing that the 5,-OH group of ribose fulfills a similar role, rather than stabilizing the oxocarbenium-like transition state. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006 [source]

Synthesis of Bicyclic N -Arylmethyl-Substituted Iminoribitol Derivatives as Selective Nucleoside Hydrolase Inhibitors

CHEMMEDCHEM, Issue 2 2009
Maya Berg
Abstract A series of bicyclicN -arylmethyl-substituted iminoribitols were synthesised and evaluated in,vitro against T.,vivax nucleoside hydrolase. The importance of the N,Asp40 interaction was confirmed and depends on an optimal pKa value, which can be influenced by substituents. The compounds were active inhibitors of nucleoside hydrolase (IAG-NH) and are inactive against human purine nucleoside phosphorylase. The purine metabolism of Trypanosoma and Leishmania spp. provides a good target in the search for new selective drugs. Bicyclic N -arylmethyl-substituted iminoribitols were developed as inhibitors of T.,vivax nucleoside hydrolase, a key enzyme of the purine salvage pathway. The obtained results and structure,activity data confirmed our model for inhibitor binding with a hydrogen bond between a nitrogen atom of the nucleobase mimetic and the protonated Asp40 from the enzyme. This interaction depends on an optimal pKa value, which can be influenced by the electronic properties of the substituents. These compounds are potent, selective inhibitors of nucleoside hydrolase and are inactive toward human nucleoside phosphorylase. [source]