Fragment Screening Hit Draws Attention to a Novel Transient Pocket Adjacent to the Recognition Site of the tRNA-Modifying Enzyme TGT
| Autor: | F. Wieland Goetzke, Tobias Hüfner-Wulsdorf, François Diederich, Christoph Hohn, Klaus Reuter, F.R. Ehrmann, Maurice Sebastiani, Adrian Härtsch, E. Hassaan, Gerhard Klebe, Levon D. Movsisyan |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Protein Conformation Drug Evaluation Preclinical Ligands medicine.disease_cause 01 natural sciences 03 medical and health sciences Drug Discovery medicine Shigella Pentosyltransferases 030304 developmental biology chemistry.chemical_classification 0303 health sciences Binding Sites Fragment (computer graphics) Ligand (biochemistry) 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Biochemistry chemistry Drug Design Transfer RNA Molecular Medicine Benzimidazoles |
| Zdroj: | Journal of Medicinal Chemistry, 63 (13) |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. © 2020 American Chemical Society. ISSN:1520-4804 ISSN:0022-2623 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|