Fragment Screening Hit Draws Attention to a Novel Transient Pocket Adjacent to the Recognition Site of the tRNA-Modifying Enzyme TGT.,Journal of Medicinal Chemistry

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Fragment Screening Hit Draws Attention to a Novel Transient Pocket Adjacent to the Recognition Site of the tRNA-Modifying Enzyme TGT.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-09 , DOI: 10.1021/acs.jmedchem.0c00115
Engi Hassaan ₁ , Christoph Hohn ₂ , Frederik R Ehrmann ₁ , F Wieland Goetzke ₂ , Levon Movsisyan ₂ , Tobias Hüfner-Wulsdorf ₁ , Maurice Sebastiani ₁ , Adrian Härtsch ₂ , Klaus Reuter ₁ , François Diederich ₂ , Gerhard Klebe ₁

Affiliation

Fragment-based lead discovery was applied to tRNA-guanine transglycosylase, an enzyme modifying post-transcriptionally tRNAs in Shigella, the causative agent of shigellosis. TGT inhibition prevents translation of Shigella’s virulence factor VirF, hence reducing pathogenicity. One discovered fragment opens a transient subpocket in the preQ₁-recognition site by pushing back an aspartate residue. This step is associated with reorganization of further amino acids structurally transforming a loop adjacent to the recognition site by duplicating the volume of the preQ₁-recognition pocket. We synthesized 6-carboxamido-, 6-hydrazido-, and 4-guanidino-benzimidazoles to target the opened pocket, including a dihydro-imidazoquinazoline with a propyn-1-yl exit vector pointing into the transient pocket and displacing a conserved water network. MD simulations and hydration-site analysis suggest water displacement to contribute favorably to ligand binding. A cysteine residue, exclusively present in bacterial TGTs, serves as gatekeeper of the transient subpocket. It becomes accessible upon pocket opening for selective covalent attachment of electrophilic ligands in eubacterial TGTs.

中文翻译：

片段筛选命中吸引人们注意与tRNA修饰酶TGT识别位点相邻的新型瞬时口袋。

基于片段的先导发现被应用于tRNA-鸟嘌呤转糖基化酶，一种修饰志贺菌的致病菌志贺氏菌中转录后tRNA的酶。TGT抑制作用可阻止志贺氏菌的毒力因子VirF的翻译，从而降低了致病性。一个发现的片段通过推回天冬氨酸残基在preQ ₁识别位点打开了一个瞬时子口袋。该步骤与其他氨基酸的重组有关，该氨基酸通过复制preQ ₁的体积在结构上转化邻近识别位点的环-识别口袋。我们合成了6-羧酰胺基，6-肼基-和4-胍基-苯并咪唑类化合物，以靶向开放的囊袋，其中包括带有氢炔基的二氢-咪唑并喹唑啉，该载体指向瞬态囊袋并置换了保守的水网。MD模拟和水合位点分析表明水置换有利于配体结合。仅存在于细菌TGT中的半胱氨酸残基充当瞬时子口袋的守门员。当口袋打开时，它就可用于在真细菌TGT中选择性共价附着亲电子配体。

更新日期：2020-07-09

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