Abstract
Aminoacyl-tRNA synthetases (aaRSs) are enzymes that catalyze the transfer of amino acids to their cognate tRNA. They play a pivotal role in protein synthesis and are essential for cell growth and survival. The aaRSs are one of the leading targets for development of antibiotic agents. In this review, we mainly focused on aaRS inhibitor discovery and development using in silico methods including virtual screening and structure-based drug design. These computational methods are relatively fast and cheap, and are proving to be of great benefit for the rational development of more potent aaRS inhibitors and other pharmaceutical agents that may usher in a much needed generation of new antibiotics.
Highlights
IntroductionAminoacyl-tRNA synthetases (aaRSs) play a central role in the process of protein synthesis
Aminoacyl-tRNA synthetases play a central role in the process of protein synthesis.They are responsible for catalyzing the attachment of the correct amino acid to its cognate tRNA through an esterification reaction at the 3' end of tRNA
Three compounds were identified as TrpRS inhibitors that arrested S. epidermidis growth from the SPECS database combining virtual screening, in vitro and in vivo experiments
Summary
Aminoacyl-tRNA synthetases (aaRSs) play a central role in the process of protein synthesis. The weakness of the additional van der Waals interactions of isoleucine compared with valine in the active site of IleRS was predicted to yield an error rate of up to one in five [5] To overcome this problem, some aaRSs have a specific editing activity that hydrolyzes misactivated aa-AMPs (pre-transfer editing) and mischarged aa-tRNAs (post-transfer editing). The second sieve occurs at an editing active site which hydrolyzes non-cognate amino acids that are misactivated or mischarged Synthetases with this additional editing site include IleRS, LeuRS, and ValRS from class I, and ThrRS, AlaRS, PheRS and ProRS from class II enzymes [6,7,8]. Inhibitors of aaRSs are being developed as antibacterials, antifungals and anti-parasitic drugs [10,11,12,13], and they possess potent immunosuppressive activity [14] Both synthetic and editing active sites are targets for inhibition. Central to all structure-based discovery approaches is experimental determination of the 3D structure of the target protein or protein-ligand complex, or construction of a suitably accurate homology model
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