Crystallographic study of in transglycosylase suggests pharmacophore for virtual hibitors of tRNA-guanine a new structure-based screening

被引:25
作者
Brenk, R
Meyer, EA
Reuter, K
Stubbs, MT
Garcia, GA
Diederich, F
Klebe, G
机构
[1] Univ Marburg, Inst Pharmazeut Chem, D-35032 Marburg, Germany
[2] ETH Honggerberg, Organ Chem Lab, HCI, CH-8093 Zurich, Switzerland
[3] Univ Michigan, Coll Pharm, Interdepartmental Program Med Chem, Ann Arbor, MI 48109 USA
关键词
TGT; crystallography; inhibitors; ligands;
D O I
10.1016/j.jmb.2004.02.019
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码:55 / 75
页数:21
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