In Silico Discovery of Aminoacyl-tRNA Synthetase Inhibitors

Zhao, Yulan; Meng, Qingqing; Bai, Linquan; Zhou, Huchen

doi:10.3390/ijms15011358

Cited by 16 publications

(12 citation statements)

References 54 publications

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“…Several bioinformatics tools are available to explore sequence and structure-derived enzyme active site residues to annotate drug inserts [143]. In silico methods including virtual screening and structure-based drug design have been used to design ARS inhibitors targeting LRS, WRS, NRS, MRS, IRS, and TRS [144][145][146]. The inhibitory activities of these compounds must be confirmed.…”

Section: Developing Bacterial Ars Inhibitorsmentioning

confidence: 99%

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Lee

Kim

2018

Biochemical Pharmacology

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Despite remarkable advances in medical science, infection-associated diseases remain among the leading causes of death worldwide. There is a great deal of interest and concern at the rate at which new pathogens are emerging and causing significant human health problems. Expanding our understanding of how cells regulate signaling networks to defend against invaders and retain cell homeostasis will reveal promising strategies against infection. It has taken scientists decades to appreciate that eukaryotic aminoacyl-tRNA synthetases (ARSs) play a role as global cell signaling mediators to regulate cell homeostasis, beyond their intrinsic function as protein synthesis enzymes. Recent discoveries revealed that ubiquitously expressed standby cytoplasmic ARSs sense and respond to danger signals and regulate immunity against infections, indicating their potential as therapeutic targets for infectious diseases. In this review, we discuss ARS-mediated anti-infectious signaling and the emerging role of ARSs in antimicrobial immunity. In contrast to their ability to defend against infection, host ARSs are inevitably co-opted by viruses for survival and propagation. We therefore provide a brief overview of the communication between viruses and the ARS system. Finally, we discuss encouraging new approaches to develop ARSs as therapeutics for infectious diseases.

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Section: Developing Bacterial Ars Inhibitorsmentioning

confidence: 99%

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Lee

Kim

2018

Biochemical Pharmacology

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“…A common class of aaRS inhibitors mimics aa-AMPs, with a non-hydrolyzable ester bond between amino acid and the alpha-phosphate, such as lysyl-sulfide adenylate or glutamyl-sulfide adenylate and other aminoacyl-sulfide adenylates (aa-SAs) (Belrhali et al, 1994; Crepin et al, 2006; Cvetesic et al, 2014; Fukai et al, 2000; Guo et al, 2009; Ito and Yokoyama, 2010; Iwasaki et al, 2006; Kamtekar et al, 2003; Kotik-Kogan et al, 2005; Nakanishi et al, 2005; Sakurama et al, 2009; Sankaranarayanan et al, 2000). Because these inhibitors directly occupy and block the active site for ATP and amino acid, they usually display high specificity and tight binding affinities (∼ nM) to aaRSs (Pope et al, 1998; Vondenhoff and Van Aerschot, 2011; Zhao et al, 2014). However due to the highly charged property of both amino acid and adenylate moieties, these inhibitors generally showed limited whole cell activity with poor penetration through the cell membrane, and their near identical structure to the natural aa-AMPs also causes poor selectivity against aaRSs from different species, limiting their potential application for therapy (Hurdle et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor

Fang

Han

Wang

et al. 2015

Chemistry & Biology

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Summary Pharmaceutical inhibitors of aminoacyl-tRNA synthetases demand high species and family specificity. The antimalarial ATP-mimetic cladosporin selectively inhibits P. falciparum LysRS (PfLysRS). How the binding to a universal ATP site achieves the specificity is unknown. Here we report 3 crystal structures of cladosporin with human LysRS, PfLysRS, and a Pf-like human LysRS mutant. In all 3 structures, cladosporin occupies the class defining ATP-binding pocket, replacing the adenosine portion of ATP. Three residues holding the methyltetrahydro-pyran moiety of cladosporin are critical for cladosporin's specificity against LysRS over other class II tRNA synthetase families. The species-exclusive inhibition of PfLysRS is linked to a structural divergence beyond the active site that mounts a lysine-specific stabilizing response to binding cladosporin. These analyses reveal that inherent divergence of tRNA synthetase structural assembly may allow for highly specific inhibition even through the otherwise universal substrate binding pocket and highlight the potential for structure driven drug development.

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“…The small number of targets that have been identified using comparative genomics has led to the suggestion that additional screening methodologies may increase the yield of viable hits [34]. Over the last two decades, multiple molecular modelling platforms have been developed that permit the in silico screening of potential inhibitors based on the proposed 3-dimensional structures of identified targets [35,36,37].…”

Section: Comparative Genomicsmentioning

confidence: 99%

Using bacterial genomes and essential genes for the development of new antibiotics

Fields

Lee

McConnell

2017

Biochemical Pharmacology

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The shrinking antibiotic development pipeline together with the global increase in antibiotic resistant infections requires that new molecules with antimicrobial activity are developed. Traditional empirical screening approaches of natural and non-natural compounds have identified the majority of antibiotics that are currently available, however this approach has produced relatively few new antibiotics over the last few decades. The vast amount of bacterial genome sequence information that has become available since the sequencing of the first bacterial genome more than 20 years ago holds potential for contributing to the discovery of novel antimicrobial compounds. Comparative genomic approaches can identify genes that are highly conserved within and between bacterial species, and thus may represent genes that participate in key bacterial processes. Whole genome mutagenesis studies can also identify genes necessary for bacterial growth and survival under different environmental conditions, making them attractive targets for the development of novel inhibitory compounds. In addition, transcriptomic and proteomic approaches can be used to characterize RNA and protein levels on a cellular scale, providing information on bacterial physiology that can be applied to antibiotic target identification. Finally, bacterial genomes can be mined to identify biosynthetic pathways that produce many intrinsic antimicrobial compounds and peptides. In this review, we provide an overview of past and current efforts aimed at using bacterial genomic data in the discovery and development of novel antibiotics.

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In Silico Discovery of Aminoacyl-tRNA Synthetase Inhibitors

Cited by 16 publications

References 54 publications

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor

Using bacterial genomes and essential genes for the development of new antibiotics

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