4hwr Citations

Identification of bacteria-selective threonyl-tRNA synthetase substrate inhibitors by structure-based design.

J. Med. Chem. 56 1748-60 (2013)
Related entries: 4hwt, 4hwo, 4hwp, 4hws

Cited: 11 times
EuropePMC logo PMID: 23362938


A series of potent and bacteria-selective threonyl-tRNA synthetase (ThrRS) inhibitors have been identified using structure-based drug design. These compounds occupied the substrate binding site of ThrRS and showed excellent binding affinities for all of the bacterial orthologues tested. Some of the compounds displayed greatly improved bacterial selectivity. Key residues responsible for potency and bacteria/human ThrRS selectivity have been identified. Antimicrobial activity has been achieved against wild-type Haemophilus influenzae and efflux-deficient mutants of Escherichia coli and Burkholderia thailandensis.

Reviews citing this publication (2)

Articles citing this publication (9)

  1. Efflux pump-mediated drug resistance in Burkholderia. Podnecky NL, Rhodes KA, Schweizer HP. Front Microbiol 6 305 (2015)
  2. Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase. Fang P, Yu X, Jeong SJ, Mirando A, Chen K, Chen X, Kim S, Francklyn CS, Guo M. Nat Commun 6 6402 (2015)
  3. Identifying the targets of aminoacyl-tRNA synthetase inhibitors by primer extension inhibition. Orelle C, Szal T, Klepacki D, Shaw KJ, Vázquez-Laslop N, Mankin AS. Nucleic Acids Res. 41 e144 (2013)
  4. Halogen-enriched fragment libraries as chemical probes for harnessing halogen bonding in fragment-based lead discovery. Zimmermann MO, Lange A, Wilcken R, Cieslik MB, Exner TE, Joerger AC, Koch P, Boeckler FM. Future Med Chem 6 617-639 (2014)
  5. Genetic validation of aminoacyl-tRNA synthetases as drug targets in Trypanosoma brucei. Kalidas S, Cestari I, Monnerat S, Li Q, Regmi S, Hasle N, Labaied M, Parsons M, Stuart K, Phillips MA. Eukaryotic Cell 13 504-516 (2014)
  6. Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor. Fang P, Han H, Wang J, Chen K, Chen X, Guo M. Chem. Biol. 22 734-744 (2015)
  7. Essentiality Assessment of Cysteinyl and Lysyl-tRNA Synthetases of Mycobacterium smegmatis. Ravishankar S, Ambady A, Swetha RG, Anbarasu A, Ramaiah S, Sambandamurthy VK. PLoS ONE 11 e0147188 (2016)
  8. Comparison of histidine recognition in human and trypanosomatid histidyl-tRNA synthetases. Koh CY, Wetzel AB, de van der Schueren WJ, Hol WG. Biochimie 106 111-120 (2014)
  9. Exploring the Molecular Basis for Binding of Inhibitors by Threonyl-tRNA Synthetase from Brucella abortus: A Virtual Screening Study. Li M, Wen F, Zhao S, Wang P, Li S, Zhang Y, Zheng N, Wang J. Int J Mol Sci 17 (2016)