Journal of Medicinal Chemistry p. 6802 - 6820 (2020)
Update date:2022-08-11
Topics:
Hassaan, Engi
Hohn, Christoph
Ehrmann, Frederik R.
Goetzke, F. Wieland
Movsisyan, Levon
Hüfner-Wulsdorf, Tobias
Sebastiani, Maurice
H?rtsch, Adrian
Reuter, Klaus
Diederich, Fran?ois
Klebe, Gerhard
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.
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Doi:10.1135/cccc20020365
(2002)Doi:10.1039/c39920001355
(1992)Doi:10.1016/S0031-9422(00)85286-3
(1970)Doi:10.1023/B:RUJO.0000043715.53702.cf
(2004)Doi:10.1007/BF00503530
(1981)Doi:10.1016/S0040-4039(00)73247-3
(1994)