Brenk Ruth, Meyer Emmanuel A, Reuter Klaus, Stubbs Milton T, Garcia George A, Diederich François, Klebe Gerhard
Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
J Mol Biol. 2004 Apr 16;338(1):55-75. doi: 10.1016/j.jmb.2004.02.019.
The enzyme tRNA-guanine transglycosylase (TGT) is involved in the pathogenicity of Shigellae. As the crystal structure of this protein is known, it is a putative target for the structure-based design of inhibitors. Here we report a crystallographic study of several new ligands exhibiting a 2,6-diamino-3H-quinazolin-4-one scaffold, which has been shown recently to be a promising template for TGT-inhibitors. Crystal structure analysis of these complexes has revealed an unexpected movement of the side-chain of Asp102. A detailed analysis of the water network disrupted by this rotation has lead to the derivation of a new composite pharmacophore. A virtual screening has been performed based on this pharmacophore hypothesis and several new inhibitors of micromolar binding affinity with new skeletons have been discovered.
酶tRNA-鸟嘌呤转糖基酶（TGT）与志贺氏菌的致病性有关。由于该蛋白质的晶体结构已知，它是基于结构的抑制剂设计的一个假定靶点。在此，我们报告了对几种具有2,6-二氨基-3H-喹唑啉-4-酮支架的新配体的晶体学研究，最近已证明该支架是TGT抑制剂的一个有前景的模板。这些复合物的晶体结构分析揭示了Asp102侧链的意外移动。对由此旋转破坏的水网络的详细分析导致了一种新的复合药效团的推导。基于该药效团假设进行了虚拟筛选，并发现了几种具有微摩尔结合亲和力且具有新骨架的新抑制剂。
