Browse
Submit Data
Databases
API
Help

Dataset Information

32 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Structure-based virtual screening and biological evaluation of Mycobacterium tuberculosis adenosine 5'-phosphosulfate reductase inhibitors.

ABSTRACT: Tuberculosis is among the world's deadliest infectious diseases. APS reductase catalyzes the first committed step in bacterial sulfate reduction and is a validated drug target against latent tuberculosis infection. We performed a virtual screening to identify APSR inhibitors. These inhibitors represent the first non-phosphate-based molecules to inhibit APSR. Common chemical features lay the foundation for the development of agents that could shorten the duration of chemotherapy by targeting the latent stage of TB infection.

SUBMITTER: Cosconati S

PROVIDER: S-EPMC2639213 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Structure-based virtual screening and biological evaluation of Mycobacterium tuberculosis adenosine 5'-phosphosulfate reductase inhibitors.

Cosconati Sandro S Hong Jiyoung A JA Novellino Ettore E Carroll Kate S KS Goodsell David S DS Olson Arthur J AJ

Journal of medicinal chemistry 20081015 21

Tuberculosis is among the world's deadliest infectious diseases. APS reductase catalyzes the first committed step in bacterial sulfate reduction and is a validated drug target against latent tuberculosis infection. We performed a virtual screening to identify APSR inhibitors. These inhibitors represent the first non-phosphate-based molecules to inhibit APSR. Common chemical features lay the foundation for the development of agents that could shorten the duration of chemotherapy by targeting the ...[more]

PMID: 18855373

Similar Datasets

Identification of critical ligand binding determinants in Mycobacterium tuberculosis adenosine-5'-phosphosulfate reductase.

Project description:Mycobacterium tuberculosis adenosine-5'-phosphosulfate (APS) reductase is an iron-sulfur protein and a validated target to develop new antitubercular agents, particularly for the treatment of latent infection. To facilitate the development of potent and specific inhibitors of APS reductase, we have probed the molecular determinants that underlie binding and specificity through a series of substrate and product analogues. Our study highlights the importance of specific substitutent groups for substrate binding and provides functional evidence for ligand-specific conformational states. An active site model has been developed for M. tuberculosis APS reductase that is in accord with the results presented here as well as prior structural data reported for Pseudomonas aeruginosa APS reductase and related enzymes. This model illustrates the functional features required for the interaction of APS reductase with a ligand and provides a pharmacological roadmap for the rational design of small molecules as potential inhibitors of APS reductase present in human pathogens, including M. tuberculosis.

| S-EPMC2749248 | biostudies-literature

Spectroscopic studies on the [4Fe-4S] cluster in adenosine 5'-phosphosulfate reductase from Mycobacterium tuberculosis.

Project description:Mycobacterium tuberculosis adenosine 5'-phosphosulfate reductase (MtAPR) is an iron-sulfur protein and a validated target to develop new antitubercular agents, particularly for the treatment of latent infection. The enzyme harbors a [4Fe-4S](2+) cluster that is coordinated by four cysteinyl ligands, two of which are adjacent in the amino acid sequence. The iron-sulfur cluster is essential for catalysis; however, the precise role of the [4Fe-4S] cluster in APR remains unknown. Progress in this area has been hampered by the failure to generate a paramagnetic state of the [4Fe-4S] cluster that can be studied by electron paramagnetic resonance spectroscopy. Herein, we overcome this limitation and report the EPR spectra of MtAPR in the [4Fe-4S](+) state. The EPR signal is rhombic and consists of two overlapping S = ½ species. Substrate binding to MtAPR led to a marked increase in the intensity and resolution of the EPR signal and to minor shifts in principle g values that were not observed among a panel of substrate analogs, including adenosine 5'-diphosphate. Using site-directed mutagenesis, in conjunction with kinetic and EPR studies, we have also identified an essential role for the active site residue Lys-144, whose side chain interacts with both the iron-sulfur cluster and the sulfate group of adenosine 5'-phosphosulfate. The implications of these findings are discussed with respect to the role of the iron-sulfur cluster in the catalytic mechanism of APR.

| S-EPMC3020729 | biostudies-literature

Design, synthesis and evaluation of Fe-S targeted adenosine 5'-phosphosulfate reductase inhibitors.

Project description:Adenosine 5'-phosphosulfate reductase (APR) is an iron-sulfur enzyme that is vital for survival of Mycobacterium tuberculosis during dormancy and is an attractive target for the treatment of latent tuberculosis (TB) infection. The 4Fe-4S cluster is coordinated to APR by sulfur atoms of four cysteine residues, is proximal to substrate, adenosine 5'-phopsphosulfate (APS), and is essential for catalytic activity. Herein, we present an approach for the development of a new class of APR inhibitors. As an initial step, we have employed an improved solid-phase chemistry method to prepare a series of N(6)-substituted adenosine analogues and their 5'-phosphates as well as adenosine 5'-phosphate diesters bearing different Fe and S binding groups, such as thiols or carboxylic and hydroxamic acid moieties. Evaluation of the resulting compounds indicates a clearly defined spacing requirement between the Fe-S targeting group and adenosine scaffold and that smaller Fe-S targeting groups are better tolerated. Molecular docking analysis suggests that the S atom of the most potent inhibitor may establish a favorable interaction with an S atom in the cluster. In summary, this study showcases an improved solid-phase method that expedites the preparation of adenosine and related 5'-phosphate derivatives and presents a unique Fe-S targeting strategy for the development of APR inhibitors.

| S-EPMC4341950 | biostudies-literature

Crystal Structure of the [4Fe-4S] Cluster-Containing Adenosine-5'-phosphosulfate Reductase from <i>Mycobacterium tuberculosis</i>.

Project description:Tuberculosis (TB) is the deadliest infectious disease in the world. In Mycobacterium tuberculosis, the first committed step in sulfate assimilation is the reductive cleavage of adenosine-5'-phosphosulfate (APS) to form adenosine-5'-phosphate (AMP) and sulfite by the enzyme APS reductase (APSR). The vital role of APSR in the production of essential reduced-sulfur-containing metabolites and the absence of a homologue enzyme in humans makes APSR a potential target for therapeutic interventions. Here, we present the crystal structure of the [4Fe-4S] cluster-containing APSR from M. tuberculosis (MtbAPSR) and compare it to previously determined structures of sulfonucleotide reductases. We further present MtbAPSR structures with substrate APS and product AMP bound in the active site. Our structures at a 3.1 Å resolution show high structural similarity to other sulfonucleotide reductases and reveal that APS and AMP have similar binding modes. These studies provide structural data for structure-based drug design aimed to combat TB.

| S-EPMC8173546 | biostudies-literature

Novel inhibitors of Mycobacterium tuberculosis dTDP-6-deoxy-L-lyxo-4-hexulose reductase (RmlD) identified by virtual screening.

Project description:The complex and highly impermeable cell wall of Mycobacterium tuberculosis (Mtb) is largely responsible for the ability of the mycobacterium to resist the action of chemical therapeutics. An L-rhamnosyl residue, which occupies an important anchoring position in the Mtb cell wall, is an attractive target for novel anti-tuberculosis drugs. In this work, we report a virtual screening (VS) study targeting Mtb dTDP-deoxy-L-lyxo-4-hexulose reductase (RmlD), the last enzyme in the L-rhamnosyl synthesis pathway. Through two rounds of VS, we have identified four RmlD inhibitors with half inhibitory concentrations of 0.9-25 μM, and whole-cell minimum inhibitory concentrations of 20-200 μg/ml. Compared with our previous high throughput screening targeting another enzyme involved in L-rhamnosyl synthesis, virtual screening produced higher hit rates, supporting the use of computational methods in future anti-tuberculosis drug discovery efforts.

| S-EPMC3223023 | biostudies-literature

Identification of Mycobacterium tuberculosis BioA inhibitors by using structure-based virtual screening.

Project description:Background7,8-Diaminopelargonic acid synthase (BioA), an enzyme of biotin biosynthesis pathway, is a well-known promising target for anti-tubercular drug development.MethodsIn this study, structure-based virtual screening was employed against the active site of BioA to identify new chemical entities for BioA inhibition and top ranking compounds were evaluated for their ability to inhibit BioA enzymatic activity.ResultsSeven compounds inhibited BioA enzymatic activity by greater than 60% at 100 ?g/mL with most potent compounds being A36, A35 and A65, displaying IC50 values of 10.48 ?g/mL (28.94 ?M), 33.36 ?g/mL (88.16 ?M) and 39.17 ?g/mL (114.42 ?M), respectively. Compounds A65 and A35 inhibited Mycobacterium tuberculosis (M. tuberculosis) growth with MIC90 of 20 ?g/mL and 80 ?g/mL, respectively, whereas compound A36 exhibited relatively weak inhibition of M. tuberculosis growth (83% inhibition at 200 ?g/mL). Compound A65 emerged as the most potent compound identified in our study that inhibited BioA enzymatic activity and growth of the pathogen and possessed drug-like properties.ConclusionOur study has identified a few hit molecules against M. tuberculosis BioA that can act as potential candidates for further development of potent anti-tubercular therapeutic agents.

| S-EPMC5935190 | biostudies-literature

Synthesis and biological evaluation of aryl-oxadiazoles as inhibitors of Mycobacterium tuberculosis.

Project description:Despite increased research efforts to find new treatments for tuberculosis in recent decades, compounds with novel mechanisms of action are still required. We previously identified a series of novel aryl-oxadiazoles with anti-tubercular activity specific for bacteria using butyrate as a carbon source. We explored the structure activity relationship of this series. Structural modifications were performed in all domains to improve potency and physico-chemical properties. A number of compounds displayed sub-micromolar activity against M. tuberculosis utilizing butyrate, but not glucose as the carbon source. Compounds showed no or low cytotoxicity against eukaryotic cells. Three compounds were profiled in mouse pharmacokinetic studies. Plasma clearance was low to moderate but oral exposure suggested solubility-limited drug absorption in addition to first pass metabolism. The presence of a basic nitrogen in the linker slightly increased solubility, and salt formation optimized aqueous solubility. Our findings suggest that the 1,3,4-oxadiazoles are useful tools and warrant further investigation.

| S-EPMC5946847 | biostudies-other

Virtual Screening of potential drug-like inhibitors against Lysine/DAP pathway of Mycobacterium tuberculosis.

Project description:BackgroundAn explosive global spreading of multidrug resistant Mycobacterium tuberculosis (Mtb) is a catastrophe, which demands an urgent need to design or develop novel/potent antitubercular agents. The Lysine/DAP biosynthetic pathway is a promising target due its specific role in cell wall and amino acid biosynthesis. Here, we report identification of potential antitubercular candidates targeting Mtb dihydrodipicolinate synthase (DHDPS) enzyme of the pathway using virtual screening protocols.ResultsIn the present study, we generated three sets of drug-like molecules in order to screen potential inhibitors against Mtb drug target DHDPS. The first set of compounds was a combinatorial library, which comprised analogues of pyruvate (substrate of DHDPS). The second set of compounds consisted of pyruvate-like molecules i.e. structurally similar to pyruvate, obtained using 3D flexible similarity search against NCI and PubChem database. The third set constituted 3847 anti-infective molecules obtained from PubChem. These compounds were subjected to Lipinski's rule of drug-like five filters. Finally, three sets of drug-like compounds i.e. 4088 pyruvate analogues, 2640 pyruvate-like molecules and 1750 anti-infective molecules were docked at the active site of Mtb DHDPS (PDB code: 1XXX used in the molecular docking calculations) to select inhibitors establishing favorable interactions.ConclusionThe above-mentioned virtual screening procedures helped in the identification of several potent candidates that possess inhibitory activity against Mtb DHDPS. Therefore, these novel scaffolds/candidates which could have the potential to inhibit Mtb DHDPS enzyme would represent promising starting points as lead compounds and certainly aid the experimental designing of antituberculars in lesser time.

| S-EPMC3009526 | biostudies-literature

Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction.

Project description:BACKGROUND: Nucleotide excision repair (NER) removes many types of DNA lesions including those induced by UV radiation and platinum-based therapy. Resistance to platinum-based therapy correlates with high expression of ERCC1, a major element of the NER machinery. The interaction between ERCC1 and XPA is essential for a successful NER function. Therefore, one way to regulate NER is by inhibiting the activity of ERCC1 and XPA. METHODOLOGY/PRINCIPAL FINDINGS: Here we continued our earlier efforts aimed at the identification and characterization of novel inhibitors of the ERCC1-XPA interaction. We used a refined virtual screening approach combined with a biochemical and biological evaluation of the compounds for their ability to interact with ERCC1 and to sensitize cells to UV radiation. Our findings reveal a new validated ERCC1-XPA inhibitor that significantly sensitized colon cancer cells to UV radiation indicating a strong inhibition of the ERCC1-XPA interaction. CONCLUSIONS: NER is a major factor in acquiring resistance to platinum-based therapy. Regulating the NER pathway has the potential of improving the efficacy of platinum treatments. One approach that we followed is to inhibit the essential interaction between the two NER elements, ERCC1 and XPA. Here, we performed virtual screening against the ERCC1-XPA interaction and identified novel inhibitors that block the XPA-ERCC1 binding. The identified inhibitors significantly sensitized colon cancer cells to UV radiation indicating a strong inhibition of the ERCC1-XPA interaction.

| S-EPMC3522735 | biostudies-literature

Virtual screening and biological evaluation of piperazine derivatives as human acetylcholinesterase inhibitors.

Project description:The piperazine derivatives have been shown to inhibit human acetylcholinesterase. Virtual screening by molecular docking of piperazine derivatives 1-(1,4-benzodioxane-2-carbonyl) piperazine (K), 4-(4-methyl)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S1), and 4-(4-chloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S3) has been shown to bind at peripheral anionic site and catalytic sites, whereas 4-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S4) and 4-(2,5-dichloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S7) do not bind either to peripheral anionic site or catalytic site with hydrogen bond. All the derivatives have differed in number of H-bonds and hydrophobic interactions. The peripheral anionic site interacting molecules have proven to be potential therapeutics in inhibiting amyloid peptides aggregation in Alzheimer's disease. All the piperazine derivatives follow Lipinski's rule of five. Among all the derivatives 1-(1,4-benzodioxane-2-carbonyl) piperazine (K) was found to have the lowest TPSA value.

| S-EPMC3830860 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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