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首页> 外文期刊>Molecular biology international >Screening the MayBridge Rule of 3 Fragment Library for Compounds That Interact with theTrypanosoma brucei myo-Inositol-3-Phosphate Synthase and/or Show Trypanocidal Activity
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Screening the MayBridge Rule of 3 Fragment Library for Compounds That Interact with theTrypanosoma brucei myo-Inositol-3-Phosphate Synthase and/or Show Trypanocidal Activity

机译：筛选3片段文库的MayBridge规则，寻找与布鲁氏锥虫肌-肌醇-3-磷酸合酶相互作用和/或显示锥虫杀灭活性的化合物

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Inositol-3-phosphate synthase (INO1) has previously been genetically validated as a drug target againstTrypanosoma brucei, the causative agent of African sleeping sickness. Chemical intervention of this essential enzyme could lead to new therapeutic agents. Unfortunately, no potent inhibitors of INO1 from any organism have been reported, so a screen for potential novel inhibitors ofT. bruceiINO1was undertaken. Detection of inhibition ofT. bruceiINO1 is problematic due to the nature of the reaction. Direct detection requires differentiation between glucose-6-phosphate and inositol-3-phosphate. Coupled enzyme assays could give false positives as potentially they could inhibit the coupling enzyme. Thus, an alternative approach of differential scanning fluorimetry to identify compounds that interact withT. bruceiINO1 was employed to screen~670 compounds from the MayBridge Rule of 3 Fragment Library. This approach identified 38 compounds, which significantly altered the Tmof TbINO1. Four compounds showed trypanocidal activity with ED50s in the tens of micromolar range, with 2 having a selectivity index in excess of 250. The trypanocidal and general cytotoxicity activities of all of the compounds in the library are also reported, with the best having ED50S of~20 μM againstT. brucei.
机译：肌醇-3-磷酸合成酶（INO1）先前已被基因验证为对抗非洲昏睡病的病原体布鲁氏锥虫的药物靶标。这种必需酶的化学干预可能会导致新的治疗剂。不幸的是，尚未报道任何生物体中INO1的有效抑制剂，因此筛选了潜在的新型T抑制剂。进行了bruceiINO1。检测抑制T。由于反应的性质，bruceiINO1有问题。直接检测需要区分6磷酸葡萄糖和3磷酸肌醇。偶联酶测定可能会产生假阳性，因为它们可能会抑制偶联酶。因此，差示扫描荧光法的另一种方法是鉴定与T相互作用的化合物。从3片段文库的MayBridge规则中使用bruceiINO1筛选了670种化合物。该方法鉴定出38种化合物，这些化合物显着改变了TbINO1的Tmof。四种化合物具有ED50在数十微摩尔范围内的锥虫杀伤活性，其中两种具有超过250的选择性指数。文库中所有化合物的锥虫杀灭和一般的细胞毒性活性也据报道，其中最好的ED50S为〜对T而言为20μm。布鲁西。

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