Computational and Experimental Druggability Assessment of Human DNA Glycosylases
Computational and Experimental Druggability Assessment of Human DNA Glycosylases
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DOI：
10.1021/acsomega.9b00162
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发表时间：
2019-07-01
期刊：
影响因子：
4.1
通讯作者：
Helleday, Thomas
中科院分区：
文献类型：
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作者：
Michel, Maurice;Visnes, Torkild;Helleday, Thomas
由于具有极性甚至带电的结合界面，dna结合蛋白被认为是开发小分子配体非常困难的靶标，迄今为止只有少数蛋白质被成功靶向。然而，最近的研究表明，开发选择性和高效的8-氧鸟嘌呤DNA糖基化酶抑制剂是可能的。在这里，我们在计算环境中描述了DNA糖基酶的初始药物性评估，并实验研究了几种用小分子抑制剂靶向内切酶VIII-like 1 （NEIL1）的方法。我们发现DNA糖基酶在DNA结合和非结合状态下都表现出良好的预测药物性。此外，我们发现催化位点高度灵活，允许一系列相互作用和结合伙伴。我们为NEIL1找到了一个灵活的催化位点，并利用存在DNA时的生化分析和不存在DNA时的热移分析对其进行了进一步的实验研究。
Due to a polar or even charged binding interface, DNA-binding proteins are considered extraordinarily difficult targets for development of small-molecule ligands and only a handful of proteins have been targeted successfully to date. Recently, however, it has been shown that development of selective and efficient inhibitors of 8-oxoguanine DNA glycosylase is possible. Here, we describe the initial druggability assessment of DNA glycosylases in a computational setting and experimentally investigate several methods to target endonuclease VIII-like 1 (NEIL1) with small-molecule inhibitors. We find that DNA glycosylases exhibit good predicted druggability in both DNA-bound and -unbound states. Furthermore, we find catalytic sites to be highly flexible, allowing for a range of interactions and binding partners. One flexible catalytic site was rationalized for NEIL1 and further investigated experimentally using both a biochemical assay in the presence of DNA and a thermal shift assay in the absence of DNA.