尿嘧啶DNA糖基化酶(UDG或Ung)是参与从DNA中切除尿嘧啶作为修复机制的关键酶。因此,设计Ung抑制剂是治疗不同癌症和传染病的有希望的策略。尿嘧啶环及其衍生物已被证明可以抑制结核分枝杆菌Ung(MtUng),由与尿嘧啶结合袋(UBP)的特异性和强结合产生。为了设计新型的Mtung抑制剂,我们筛选了几种非尿嘧啶环片段,这些片段由于与尿嘧啶结构基序的高度相似性而被假设占据了MtUngUBP。这些努力导致了新的MtUng环抑制剂的发现。在这里,我们报告了这些碎片的共晶姿势,确认它们在UBP中的约束力,从而为新型先导化合物的设计提供了强大的结构框架。我们选择巴比妥酸(BA)环作为进一步衍生化和SAR分析的案例研究。建模研究预测了设计类似物的BA环与MtUngUBP相互作用,就像尿嘧啶环一样。使用放射性和基于荧光的测定在体外筛选合成的化合物。这些研究导致了一种新型的基于BA的MtUng抑制剂18a(IC50=300μM),其效力超过尿嘧啶环24倍。
Uracil DNA glycosylase (UDG or Ung) is a key enzyme involved in
uracil excision from the DNA as a repair mechanism. Designing Ung inhibitors is thus a promising strategy to treat different cancers and infectious diseases. The
uracil ring and its derivatives have been shown to inhibit Mycobacterium tuberculosis Ung (MtUng), resulting from specific and strong binding with the
uracil-binding pocket (UBP). To design novel MtUng inhibitors, we screened several non-uracil ring fragments hypothesised to occupy MtUng UBP due to their high similarity to the
uracil structural motif. These efforts have resulted in the discovery of novel MtUng ring inhibitors. Here we report the co-crystallised poses of these fragments, confirming their binding within the UBP, thus providing a robust structural framework for the design of novel lead compounds. We selected the barbituric acid (BA) ring as a
case study for further derivatisation and SAR analysis. The modelling studies predicted the BA ring of the designed analogues to interact with the MtUng UBP much like the uracil ring. The synthesised compounds were screened in vitro using radioactivity and a fluorescence-based assay. These studies led to a novel BA-based MtUng inhibitor 18a (IC50 = 300 μM) displaying ∼24-fold potency over the uracil ring.