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Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

DOI: 10.1021/acs.jmedchem.9b01131 DOI Help

Authors: Ricky Cain (University of Warwick) , Ramya Salimraj (University of Warwick) , Avinash Punekar (University of Warwick) , Dom Belini (University of Warwick) , Colin W. G. Fishwick (University of Leeds) , Lloyd Czaplewski (Chemical Biology Ventures Limited) , David Jan Scott (University of Nottingham; ISIS Spallation Neutron and Muon Source and the Research Complex at Harwell) , Gemma Harris (ISIS Spallation Neutron and Muon Source and the Research Complex at Harwell) , Christopher G. Dowson (University of Warwick) , Adrian J. Lloyd (University of Warwick) , David I. Roper (University of Warwick)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: October 2019
Diamond Proposal Number(s): 14692

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 two orders of magnitude compared to their human homologue, demonstrating a route to selective chemical inhibition of these bacterial targets.

Diamond Keywords: Enzymes; Bacteria

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 21/10/2019 09:48

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)