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Publication Abstract from PubMed

Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani. To date, all kinetoplastid MetRS inhibitors described bind in a similar way to an expanded methionine pocket and an adjacent, auxiliary pocket. In the current study, we have identified a structurally novel class of inhibitors containing a 4,6-diamino-substituted pyrazolopyrimidine core (the MetRS02 series). Crystallographic studies revealed that MetRS02 compounds bind to an allosteric pocket in L. major MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the Trypanosoma cruzi MetRS enzyme revealed key differences in the allosteric pocket between the T. cruzi and Leishmania enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the T. cruzi enzyme compared to the Leishmania enzyme. The identification of a new series of MetRS inhibitors and the discovery of a new binding site in kinetoplastid MetRS enzymes provide a novel strategy in the search for new therapeutics for kinetoplastid diseases.

Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase.,Torrie LS, Robinson DA, Thomas MG, Hobrath JV, Shepherd SM, Post JM, Ko EJ, Ferreira RA, Mackenzie CJ, Wrobel K, Edwards DP, Gilbert IH, Gray DW, Fairlamb AH, De Rycker M ACS Infect Dis. 2020 May 8;6(5):1044-1057. doi: 10.1021/acsinfecdis.9b00453. Epub, 2020 Apr 28. PMID:32275825^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.