Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Computer-aided discovery of Trypanosoma brucei RNA-editing terminal uridylyl transferase 2 inhibitors.

ABSTRACT: Human African trypanosomiasis (HAT) is a major health problem in sub-Saharan Africa caused by Trypanosoma brucei infection. Current HAT drugs are difficult to administer and not effective against all parasite species at different stages of the disease which indicates an unmet pharmaceutical need. TbRET2 is an indispensable enzyme for the parasite and is targeted here using a computational approach that combines molecular dynamics simulations and virtual screening. The compounds prioritized are then tested in T. brucei via Alamar blue cell viability assays. This work identified 20 drug-like compounds which are candidates for further testing in the drug discovery process.

SUBMITTER: Demir O

PROVIDER: S-EPMC4317284 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Computer-aided discovery of Trypanosoma brucei RNA-editing terminal uridylyl transferase 2 inhibitors.

Demir Ozlem O Labaied Mehdi M Merritt Chris C Stuart Ken K Amaro Rommie E RE

Chemical biology & drug design 20140605 2

Human African trypanosomiasis (HAT) is a major health problem in sub-Saharan Africa caused by Trypanosoma brucei infection. Current HAT drugs are difficult to administer and not effective against all parasite species at different stages of the disease which indicates an unmet pharmaceutical need. TbRET2 is an indispensable enzyme for the parasite and is targeted here using a computational approach that combines molecular dynamics simulations and virtual screening. The compounds prioritized are t ...[more]

PMID: 24903413

Similar Datasets

The EIF4E1-4EIP cap-binding complex of Trypanosoma brucei interacts with the terminal uridylyl transferase TUT3

Project description:Most transcription in Trypanosoma brucei is constitutive and polycistronic. Consequently, the parasite relies on post-transcriptional mechanisms, especially affecting translation initiation and mRNA decay, to control gene expression both at steady-state and for adaptation to different environments. The parasite has six isoforms of the cap-binding protein EIF4E as well as five EIF4Gs. EIF4E1 does not bind to any EIF4G, instead being associated with a 4E-binding protein, 4EIP. 4EIP represses translation and reduces the stability of a reporter mRNA when artificially tethered to the 3’-UTR, whether or not EIF4E1 is present. 4EIP is essential during the transition from the mammalian bloodstream form to the procyclic form that lives in the Tsetse vector. In contrast, EIF4E1 is dispensable during differentiation, but is required for establishment of growing procyclic forms. In Leishmania, there is some evidence that EIF4E1 might be active in translation initiation, via direct recruitment of EIF3. However in T. brucei, EIF4E1 showed no detectable association with other translation initiation factors, even in the complete absence of 4EIP. There was some evidence for interactions with NOT complex components, but if these occur they must be weak and transient. We found that EIF4E1is less abundant in the absence of 4EIP, and RNA pull-down results suggested this might occur through co-translational complex assembly. We also report that 4EIP directly recruits the cytosolic terminal uridylyl transferase TUT3 to EIF4E1/4EIP complexes. There was, however, no evidence that TUT3 is essential for 4EIP function.

| S-EPMC8608314 | biostudies-literature

Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei.

Project description:Trypanosomatid RNA editing is a unique process and essential for these organisms. It therefore represents a drug target for a group of protozoa that includes the causative agents for African sleeping sickness and other devastating tropical and subtropical diseases. Here, we present drug-like inhibitors of a key enzyme in the editing machinery, RNA-editing ligase 1 (REL1). These inhibitors were identified through a strategy employing molecular dynamics to account for protein flexibility. A virtual screen of the REL1 crystal structure against the National Cancer Institute Diversity Set was performed by using AutoDock4. The top 30 compounds, predicted to interact with REL1's ATP-binding pocket, were further refined by using the relaxed complex scheme (RCS), which redocks the compounds to receptor structures extracted from an explicitly solvated molecular dynamics trajectory. The resulting reordering of the ligands and filtering based on drug-like properties resulted in an initial recommended set of 8 ligands, 2 of which exhibited micromolar activity against REL1. A subsequent hierarchical similarity search with the most active compound over the full National Cancer Institute database and RCS rescoring resulted in an additional set of 6 ligands, 2 of which were confirmed as REL1 inhibitors with IC(50) values of approximately 1 microM. Tests of the 3 most promising compounds against the most closely related bacteriophage T4 RNA ligase 2, as well as against human DNA ligase IIIbeta, indicated a considerable degree of selectivity for RNA ligases. These compounds are promising scaffolds for future drug design and discovery efforts against these important pathogens.

| S-EPMC2577703 | biostudies-literature

Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors.

Project description:The Ebola virus (EBOV) causes severe human infection that lacks effective treatment. A recent screen identified a series of compounds that block EBOV-like particle entry into human cells. Using data from this screen, quantitative structure-activity relationship models were built and employed for virtual screening of a ∼17 million compound library. Experimental testing of 102 hits yielded 14 compounds with IC50 values under 10 μM, including several sub-micromolar inhibitors, and more than 10-fold selectivity against host cytotoxicity. These confirmed hits include FDA-approved drugs and clinical candidates with non-antiviral indications, as well as compounds with novel scaffolds and no previously known bioactivity. Five selected hits inhibited BSL-4 live-EBOV infection in a dose-dependent manner, including vindesine (0.34 μM). Additional studies of these novel anti-EBOV compounds revealed their mechanisms of action, including the inhibition of NPC1 protein, cathepsin B/L, and lysosomal function. Compounds identified in this study are among the most potent and well-characterized anti-EBOV inhibitors reported to date.

| S-EPMC6548547 | biostudies-literature

Computer-aided identification of Trypanosoma brucei uridine diphosphate galactose 4'-epimerase inhibitors: toward the development of novel therapies for African sleeping sickness.

Project description:Trypanosoma brucei, the causative agent of human African trypanosomiasis, affects tens of thousands of sub-Saharan Africans. As current therapeutics are inadequate due to toxic side effects, drug resistance, and limited effectiveness, novel therapies are urgently needed. UDP-galactose 4'-epimerase (TbGalE), an enzyme of the Leloir pathway of galactose metabolism, is one promising T. brucei drug target. We here use the relaxed complex scheme, an advanced computer-docking methodology that accounts for full protein flexibility, to identify inhibitors of TbGalE. An initial hit rate of 62% was obtained at 100 microM, ultimately leading to the identification of 14 low-micromolar inhibitors. Thirteen of these inhibitors belong to a distinct series with a conserved binding motif that may prove useful in future drug design and optimization.

| S-EPMC2895357 | biostudies-literature

Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1.

Project description:Neglected tropical diseases, including diseases caused by trypanosomatid parasites such as Trypanosoma brucei, cost tens of millions of disability-adjusted life-years annually. As the current treatments for African trypanosomiasis and other similar infections are limited, new therapeutics are urgently needed. RNA Editing Ligase 1 (REL1), a protein unique to trypanosomes and other kinetoplastids, was identified recently as a potential drug target.Motivated by the urgent need for novel trypanocidal therapeutics, we use an ensemble-based virtual-screening approach to discover new naphthalene-based TbREL1 inhibitors. The predicted binding modes of the active compounds are evaluated within the context of the flexible receptor model and combined with computational fragment mapping to determine the most likely binding mechanisms. Ultimately, four new low-micromolar inhibitors are presented. Three of the four compounds may bind to a newly revealed cleft that represents a putative druggable site not evident in any crystal structure.Pending additional optimization, the compounds presented here may serve as precursors for future novel therapies useful in the fight against several trypanosomatid pathogens, including human African trypanosomiasis, a devastating disease that afflicts the vulnerable patient populations of sub-Saharan Africa.

| S-EPMC2927429 | biostudies-literature

Computer-aided discovery of phenylpyrazole based amides as potent S6K1 inhibitors.

Project description:Ribosomal protein S6 kinase beta-1 (S6K1) is an attractive therapeutic target. In this study, computational analysis of five thiophene urea-based S6K1 inhibitors was performed. Molecular docking showed that the five compounds formed hydrogen bonds with residues Glu173 and Leu175 of S6K1 and hydrophobic interactions with residues Val105, Leu97 and Met225, and these interactions were key elements for the inhibitory potency of the compounds. Binding free energy (ΔG bind) decomposition analysis showed that Leu97, Glu173, Val 105, Leu175, Leu97 and Met225 contribute the most to ΔG bind. Based on the computer results, phenylpyrazole based amides (D1-D3) were designed and synthesized. Biological evaluation revealed that D2 exhibited 15.9 nM S6K1 inhibition, medium microsomal stability and desirable bioavailability.

| S-EPMC7605259 | biostudies-literature

Towards the development of novel Trypanosoma brucei RNA editing ligase 1 inhibitors.

Project description:Trypanosoma brucei (T. brucei) is an infectious agent for which drug development has been largely neglected. We here use a recently developed computer program called AutoGrow to add interacting molecular fragments to S5, a known inhibitor of the validated T. brucei drug target RNA editing ligase 1, in order to improve its predicted binding affinity.The proposed binding modes of the resulting compounds mimic that of ATP, the native substrate, and provide insights into novel protein-ligand interactions that may be exploited in future drug-discovery projects.We are hopeful that these new predicted inhibitors will aid medicinal chemists in developing novel therapeutics to fight human African trypanosomiasis.

| S-EPMC3196686 | biostudies-literature

Discovery of potent and selective inhibitors of Trypanosoma brucei ornithine decarboxylase.

Project description:Human African trypanosomiasis, caused by the eukaryotic parasite Trypanosoma brucei, is a serious health problem in much of central Africa. The only validated molecular target for treatment of human African trypanosomiasis is ornithine decarboxylase (ODC), which catalyzes the first step in polyamine metabolism. Here, we describe the use of an enzymatic high throughput screen of 316,114 unique molecules to identify potent and selective inhibitors of ODC. This screen identified four novel families of ODC inhibitors, including the first inhibitors selective for the parasitic enzyme. These compounds display unique binding modes, suggesting the presence of allosteric regulatory sites on the enzyme. Docking of a subset of these inhibitors, coupled with mutagenesis, also supports the existence of these allosteric sites.

| S-EPMC2878083 | biostudies-literature

Structural basis for the activity of a cytoplasmic RNA terminal uridylyl transferase.

Project description:Cytoplasmic terminal uridylyl transferases comprise a conserved family of enzymes that negatively regulate the stability or biological activity of a variety of eukaryotic RNAs, including mRNAs and tumor-suppressor let-7 microRNAs. Here we describe crystal structures of the Schizosaccharomyces pombe cytoplasmic terminal uridylyl transferase Cid1 in two apo conformers and bound to UTP. We demonstrate that a single histidine residue, conserved in mammalian Cid1 orthologs, is responsible for discrimination between UTP and ATP. We also describe a new high-affinity RNA substrate-binding mechanism of Cid1, which is essential for enzymatic activity and is mediated by three basic patches across the surface of the enzyme. Overall, our structures provide a basis for understanding the activity of Cid1 and a mechanism of UTP selectivity conserved in its human orthologs, suggesting potential implications for anticancer drug design.

| S-EPMC4342108 | biostudies-literature

Responsive fluorescent nucleotides serve as efficient substrates to probe terminal uridylyl transferase.

Project description:We repurposed a terminal uridylyl transferase enzyme to site-specifically label RNA with microenvironment sensing fluorescent nucleotide mimics, which in turn provided direct read-outs to estimate the binding affinities of the enzyme to RNA and nucleotide substrates. This enzyme-probe system provides insights into the catalytic cycle, and can facilitate the development of discovery platforms to identify robust enzyme inhibitors.

| S-EPMC7611084 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data