ArticleJournal of computer-aided molecular design2006
Discovering new classes of Brugia malayi asparaginyl-tRNA synthetase inhibitors and relating specificity to conformational change.
Article in Journal of computer-aided molecular design, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 47 citations in OpenAlex.
- Pharmacoinformatics-based screening of active compounds from Vitex negundo against lymphatic filariasis by targeting asparaginyl-tRNA synthetase.Journal of molecular modeling · 2023Article
- Discovery, isolation, heterologous expression and mode-of-action studies of the antibiotic polyketide tatiomicin from Amycolatopsis sp. DEM30355.Scientific reports · 2022Article
- Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics.The Journal of biological chemistry · 2019Review
- Protein-ligand interfaces are polarized: discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes.Journal of computer-aided molecular design · 2018Article
- Virtual screening of traditional Chinese medicine (TCM) database: identification of fragment-like lead molecules for filariasis target asparaginyl-tRNA synthetase.Journal of molecular modeling · 2014Article
- Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites.International journal for parasitology. Drugs and drug resistance · 2014Review
- In silico discovery of aminoacyl-tRNA synthetase inhibitors.International journal of molecular sciences · 2014Review
- Recent advances in cyclonucleosides: C-cyclonucleosides and spore photoproducts in damaged DNA.Molecules (Basel, Switzerland) · 2012Review
- Using structural analysis to generate parasite-selective monoclonal antibodies.Protein science : a publication of the Protein Society · 2008Article
- Flexible ligand docking to multiple receptor conformations: a practical alternative.Current opinion in structural biology · 2008Review
- IA, database of known ligands of aminoacyl-tRNA synthetases.Journal of computer-aided molecular design · 2007Article
- Article
- Structural basis for the enantiospecificities of R- and S-specific phenoxypropionate/alpha-ketoglutarate dioxygenases.Protein science : a publication of the Protein Society · 2006Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 6 countries.
Funding
Abstract
SLIDE software, which models the flexibility of protein and ligand side chains while docking, was used to screen several large databases to identify inhibitors of Brugia malayi asparaginyl-tRNA synthetase (AsnRS), a target for anti-parasitic drug design. Seven classes of compounds identified by SLIDE were confirmed as micromolar inhibitors of the enzyme. Analogs of one of these classes of inhibitors, the long side-chain variolins, cannot bind to the adenosyl pocket of the closed conformation of AsnRS due to steric clashes, though the short side-chain variolins identified by SLIDE apparently bind isosterically with adenosine. We hypothesized that an open conformation of the motif 2 loop also permits the long side-chain variolins to bind in the adenosine pocket and that their selectivity for Brugia relative to human AsnRS can be explained by differences in the sequence and conformation of this loop. Loop flexibility sampling using Rigidity Optimized Conformational Kinetics (ROCK) confirms this possibility, while scoring of the relative affinities of the different ligands by SLIDE correlates well with the compounds' ranks in inhibition assays. Combining ROCK and SLIDE provides a promising approach for exploiting conformational flexibility in structure-based screening and design of species selective inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.