Abstract
Methione tRNA synthetase (MetRS) is an essential enzyme involved in protein biosynthesis in all living organisms and is a potential antibacterial target. In the current study, the structure-based pharmacophore (SBP)-guided method has been suggested to generate a comprehensive pharmacophore of MetRS based on fourteen crystal structures of MetRS-inhibitor complexes. In this investigation, a hybrid protocol of a virtual screening method, comprised of pharmacophore model-based virtual screening (PBVS), rigid and flexible docking-based virtual screenings (DBVS), is used for retrieving new MetRS inhibitors from commercially available chemical databases. This hybrid virtual screening approach was then applied to screen the Specs (202,408 compounds) database, a structurally diverse chemical database. Fifteen hit compounds were selected from the final hits and shifted to experimental studies. These results may provide important information for further research of novel MetRS inhibitors as antibacterial agents.
Highlights
Translation is one of the most complex biological processes and involves diverse protein factors and enzymes, as well as messenger and transfer RNAs [1]
Optimization for the docking parameters and scoring functions was done in advance, because docking parameters and scoring functions have an important influence on the performance of molecular docking-based virtual screening
Compounds ZINC06843697 and ZINC00729256, which are different in their chemical scaffolds, were identified as promising novel leads against Methione tRNA synthetase (MetRS) with good MIC value of pathogenic bacteria and non-cytotoxicity to Human Embryonic Kidney 293 cell line (HEK293) cell
Summary
Translation is one of the most complex biological processes and involves diverse protein factors and enzymes, as well as messenger and transfer RNAs [1]. The activities of aminoacyl-tRNA synthetases are essential in all living organisms, the selective inhibition of pathogen synthetases over their human cellular counterparts provides an attractive antibacterial mode of action for discovering novel classes of antibiotics, for the treatment of antibiotic-resistant bacterial strains and Trypanosoma brucei. Tandon et al performed high-throughput screening to identify oxazolone-dipeptides that showed selectivity for SaMetRS versus human MetRS (hMetRS) [14]. Lee et al reported pyrazole derivatives inhibitors of methionyl-tRNA synthetase (MetRS) by high-throughput screening, which bear modest micromolar inhibiting properties of the bacterial MetRS enzyme from SaMetRS and Enterococci faecalis methionyl-tRNA synthetase (EfMetRS), but with weak selectivity to hMetRS [15]. Our research group aimed at searching for novel potent antimicrobial compounds [17], and we attempted to explore accurate and reasonable methodology of hybrid structure-based pharmacophore and virtual screening methods. The results might be helpful in understanding the inhibitory mechanism and in future discovery of novel antibacterial compounds
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