1 research outputs found
Structural Basis for Inhibition of Mycobacterial and Human Adenosine Kinase by 7‑Substituted 7‑(Het)aryl-7-deazaadenine Ribonucleosides
Adenosine kinase (ADK) from <i>Mycobacterium tuberculosis</i> (Mtb) was selected as a target
for design of antimycobacterial nucleosides.
Screening of 7-(het)aryl-7-deazaadenine ribonucleosides with Mtb and
human (<i>h</i>) ADKs and testing with wild-type and drug-resistant
Mtb strains identified specific inhibitors of Mtb ADK with micromolar
antimycobacterial activity and low cytotoxicity. X-ray structures
of complexes of Mtb and <i>h</i>ADKs with 7-ethynyl-7-deazaadenosine
showed differences in inhibitor interactions in the adenosine binding
sites. 1D <sup>1</sup>H STD NMR experiments revealed that these inhibitors
are readily accommodated into the ATP and adenosine binding sites
of Mtb ADK, whereas they bind preferentially into the adenosine site
of <i>h</i>ADK. Occupation of the Mtb ADK ATP site with
inhibitors and formation of catalytically less competent semiopen
conformation of MtbADK after inhibitor binding in the adenosine site
explain the lack of phosphorylation of 7-substituted-7-deazaadenosines.
Semiempirical quantum mechanical analysis confirmed different affinity
of nucleosides for the Mtb ADK adenosine and ATP sites