Michel Maurice, Visnes Torkild, Homan Evert J, Seashore-Ludlow Brinton, Hedenström Mattias, Wiita Elisée, Vallin Karl, Paulin Cynthia B J, Zhang Jiaxi, Wallner Olov, Scobie Martin, Schmidt Andreas, Jenmalm-Jensen Annika, Warpman Berglund Ulrika, Helleday Thomas
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden.
Department of Biotechnology and Nanomedicine, SINTEF Industry, N-7465 Trondheim, Norway.
ACS Omega. 2019 Jul 5;4(7):11642-11656. doi: 10.1021/acsomega.9b00162. eCollection 2019 Jul 31.
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.
由于存在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极具挑战性的靶点，迄今为止只有少数几种蛋白成功成为靶点。然而，最近有研究表明，开发8-氧代鸟嘌呤DNA糖基化酶的选择性高效抑制剂是可行的。在此，我们在计算环境中描述了DNA糖基化酶的初始可成药性评估，并通过实验研究了几种用小分子抑制剂靶向类内切核酸酶VIII样1（NEIL1）的方法。我们发现，DNA糖基化酶在DNA结合和未结合状态下均表现出良好的预测可成药性。此外，我们发现催化位点具有高度灵活性，能够产生一系列相互作用和结合伙伴。我们对NEIL1的一个灵活催化位点进行了合理化分析，并在有DNA存在的情况下通过生化分析以及在无DNA的情况下通过热位移分析进行了进一步的实验研究。
