2. Academic Validation
  3. Structure-Guided Enhancement of Selectivity of Chemical Probe Inhibitors Targeting Bacterial Seryl-tRNA Synthetase

Structure-Guided Enhancement of Selectivity of Chemical Probe Inhibitors Targeting Bacterial Seryl-tRNA Synthetase

  • J Med Chem. 2019 Nov 14;62(21):9703-9717. doi: 10.1021/acs.jmedchem.9b01131.
Ricky Cain 1,  Ramya Salimraj 1,  Avinash S Punekar 1,  Dom Bellini 1,  Colin W G Fishwick 2,  Lloyd Czaplewski 3,  David J Scott 4 5,  Gemma Harris 5,  Christopher G Dowson 1,  Adrian J Lloyd 1,  David I Roper 1
Affiliations

Affiliations

  • 1 School of Life Sciences , University of Warwick , Gibbet Hill Road , Coventry CV4 7AL , United Kingdom.
  • 2 School of Chemistry , University of Leeds , Leeds LS2 9JT , United Kingdom.
  • 3 Chemical Biology Ventures Limited , Abingdon OX14 1XD , United Kingdom.
  • 4 School of Biosciences , University of Nottingham , Nottingham LE12 5RD , United Kingdom.
  • 5 ISIS Spallation Neutron and Muon Source and the Research Complex at Harwell , Rutherford Appleton Laboratory , Oxfordshire OX11 0FA , United Kingdom.
PMID: 31626547 DOI: 10.1021/acs.jmedchem.9b01131
Abstract

Aminoacyl-tRNA synthetases are ubiquitous and essential Enzymes for protein synthesis and also a variety of other metabolic processes, especially in Bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and Antibiotic resistance generation can be addressed. We have determined high-resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit Bacterial seryl-tRNA synthetases with greater than 2 orders of magnitude compared to their human homologue, demonstrating a route to the selective chemical inhibition of these Bacterial targets.

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  • HY-160127
    化学探针
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