Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
ACS Infect Dis. 2020 May 8;6(5):1044-1057. doi: 10.1021/acsinfecdis.9b00453. Epub 2020 Apr 28.
Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites and . 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 MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the MetRS enzyme revealed key differences in the allosteric pocket between the and enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the enzyme compared to the 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.
甲硫氨酰-tRNA 合成酶（MetRS）是动质体寄生虫中经过化学验证的药物靶点，。迄今为止，所有描述的动质体 MetRS 抑制剂都以类似的方式结合到扩展的蛋氨酸口袋和相邻的辅助口袋中。在本研究中，我们已经鉴定出一类结构新颖的抑制剂，其包含 4,6-二氨基取代的吡唑并嘧啶核心（MetRS02 系列）。晶体学研究表明，MetRS02 化合物结合到以前未描述的 MetRS 的别构口袋中，酶学研究表明其抑制模式为非竞争性。同源建模表明，MetRS 酶的别构口袋在 和 酶之间存在关键差异。这可能解释了我们观察到的 MetRS02 对 酶的效力低于对 酶的效力。新型 MetRS 抑制剂系列的发现和动质体 MetRS 酶中新的结合位点的发现为寻找动质体疾病的新疗法提供了新策略。
