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
Engi HassaanGerhard Klebe

Abstract

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.

References

Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Jul 23, 2004·The Journal of Chemical Physics·Hans W HornTeresa Head-Gordon
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Feb 13, 2008·Journal of the American Chemical Society·Robert AbelRichard A Friesner
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Sep 12, 2009·Chemistry : a European Journal·Philipp C KohlerFrançois Diederich
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Aug 6, 2010·The Cochrane Database of Systematic Reviews·Prince Rh ChristopherVenkatesan Sankarapandian
May 15, 2012·Journal of Chemical Theory and Computation·Andreas W GötzRoss C Walker
Feb 5, 2014·Journal of Chemical Information and Modeling·Diane Joseph-McCarthyDemetri Moustakas
Sep 10, 2013·Journal of Chemical Theory and Computation·Romelia Salomon-FerrerRoss C Walker
Mar 23, 2017·Journal of Medicinal Chemistry·Zheng ZhaoPhilip E Bourne
Oct 11, 2017·Angewandte Chemie·Apirat ChaikuadStefan Knapp
Jul 27, 2018·Current Opinion in Infectious Diseases·Stephen Baker, Hao Chung The
Aug 24, 2018·Journal of Medicinal Chemistry·Joseph SchoepferPascal Furet

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Citations

Aug 28, 2020·Frontiers in Molecular Biosciences·Qingxin Li
Dec 21, 2021·Journal of Medicinal Chemistry·Iwan J P de EschLouise Walsh

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