Mycobacterium Cytidylate Kinase Appears to Be an Undruggable Target.
Mycobacterium Cytidylate Kinase Appears to Be an Undruggable Target.
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分枝杆菌胞化酸酯激酶似乎是一个不难的靶标。
DOI：
10.1177/1087057116646702
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发表时间：
2016-08
影响因子：
--
通讯作者：
Van Voorhis WC
中科院分区：
文献类型：
--
作者：
Craig JK;Risler JK;Loesch KA;Dong W;Baker D;Barrett LK;Subramanian S;Samudrala R;Van Voorhis WC
随着结核病的多重耐药形式变得更加普遍，迫切需要新的和改进的治疗结核病的药物。结核分枝杆菌胞苷酸激酶因其重要性和对人类同源基因不同的底物特异性而成为一个有吸引力的筛选靶点。然而，我们选择耻垢分枝杆菌胞苷酸激酶进行筛选，是因为可以获得定义其结构的高分辨率X射线结晶学数据，并且活性部位结构与结核分枝杆菌同源物的结构相似的可能性很高。我们报道了一种基于荧光素酶的高通量活性测定的开发和实施，并从小分子文库中筛选出19920个化合物，并在电子计算机上筛选预测胞苷酸激酶酶的可能抑制剂。HIT验证包括对荧光素酶抑制剂的计数器筛查，该筛查会导致初始筛查中的假阳性。这一反筛选的结果排除了在初始筛选中确定的所有假定的胞苷酸激酶抑制剂，没有留下任何化合物作为药物开发的候选。尽管结果是否定的，但这项研究表明，这个重要的药物靶点实际上可能是无法下药的，并为未来的调查提供了一个警告。
New and improved drugs against tuberculosis are urgently needed as multi-drug resistant forms of the disease become more prevalent. Mycobacterium tuberculosis cytidylate kinase is an attractive target for screening due to its essentiality and different substrate specificity to the human orthologue. However, we selected the Mycobacterium smegmatis cytidylate kinase for screening because of the availability of high resolution X-ray crystallographic data defining its structure and the high likelihood of active site structural similarity to the Mycobacterium tuberculosis orthologue. We report the development and implementation of a high-throughput luciferase based activity assay and screening of 19,920 compounds derived from small molecule libraries and an in-silico screen predicting likely inhibitors of the cytidylate kinase enzyme. Hit validation included a counter screen for luciferase inhibitors that would result in false positives in the initial screen. Results of this counter screen ruled out all of the putative cytidylate kinase inhibitors identified in the initial screening, leaving no compounds as candidates for drug development. Although a negative result, this study indicates that this important drug target may in fact be undruggable and serve as a warning for future investigations.
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影响因子：
12.3
作者：
Boutros M;Brás LP;Huber W
通讯作者：
Huber W
影响因子：
5.7
作者：
Briozzo, P;Golinelli-Pimpaneau, B;Bârzu, O
通讯作者：
Bârzu, O
影响因子：
--
作者：
Crowther, Gregory J.;Napuli, Alberto J.;Van Voorhis, Wesley C.
通讯作者：
Van Voorhis, Wesley C.
高分辨率表型分析定义了对分枝杆菌生长和胆固醇分解代谢必不可少的基因。
影响因子：
6.7
作者：
Griffin JE;Gawronski JD;Dejesus MA;Ioerger TR;Akerley BJ;Sassetti CM
通讯作者：
Sassetti CM
DOI：
10.2174/1389557515666150219145148
发表时间：
2015
期刊：
Mini reviews in medicinal chemistry
影响因子：
--
作者：
Sethi G;Chopra G;Samudrala R
通讯作者：
Samudrala R