Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase.

ABSTRACT: N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor 3. Further structure-based inhibitor design led to the discovery of 30, the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub-?M anti-plasmodial activity.

SUBMITTER: Yu Z

PROVIDER: S-EPMC4757856 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase.

Yu Zhiyong Z Brannigan James A JA Rangachari Kaveri K Heal William P WP Wilkinson Anthony J AJ Holder Anthony A AA Leatherbarrow Robin J RJ Tate Edward W EW

MedChemComm 20150819 10

N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular ...[more]

PMID: 26962430

Similar Datasets

Discovery of novel and ligand-efficient inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferase.

Project description:N-Myristoyltransferase (NMT) is an attractive antiprotozoan drug target. A lead-hopping approach was utilized in the design and synthesis of novel benzo[b]thiophene-containing inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) NMT. These inhibitors are selective against Homo sapiens NMT1 (HsNMT), have excellent ligand efficiency (LE), and display antiparasitic activity in vitro. The binding mode of this series was determined by crystallography and shows a novel binding mode for the benzothiophene ring.

| S-EPMC3601602 | biostudies-literature

Design and synthesis of inhibitors of Plasmodium falciparum N-myristoyltransferase, a promising target for antimalarial drug discovery.

Project description:Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum , the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.

| S-EPMC3863768 | biostudies-literature

Characterization of N-myristoyltransferase from Plasmodium falciparum.

Project description:The gene coding for myristoyl-CoA:protein N-myristoyltransferase (NMT) has been cloned from the malaria parasite Plasmodium falciparum. The gene appears to be single copy and mRNA is expressed in asexual blood-stage forms. Comparison of cDNA and genomic sequences identified three small introns. The open reading frame codes for a 410-amino-acid protein and no evidence of forms with an extended N-terminal coding sequence was obtained. Residues important in substrate binding and in the catalytic mechanism in other species are conserved. The protein was expressed from a plasmid in Escherichia coli, partially purified and shown to have enzymic activity using a synthetic peptide substrate. Comparison of the malaria parasite protein with that derived from the human gene showed a different pattern of inhibition by chemical modification. Human NMT activity was inhibited by diethylpyrocarbonate and partially inhibited by iodacetamide, whereas P. falciparum NMT activity was not inhibited by either pre-treatment. Since the enzyme in infectious fungi is a target for potential chemotherapeutic drugs, it should also be investigated in the context of parasitic infections such as that responsible for malaria.

| S-EPMC1221086 | biostudies-other

Discovery of isoxazolyl-based inhibitors of Plasmodium falciparum cGMP-dependent protein kinase.

Project description:The cGMP-dependent protein kinase in Plasmodium falciparum (PfPKG) plays multiple roles in the life cycle of the parasite. As a result, this enzyme is a potential target for new antimalarial agents. Existing inhbitors, while potent and active in malaria models are not optimal. This communication describes initial optimization of a structurally distinct class of PfPKG inhibitors.

| S-EPMC7536641 | biostudies-literature

Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.

Project description:The discovery of new targets for the treatment of malaria, in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this paper presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity, and cell-based antiparasitic activity against multiple Plasmodium species that appears to be correlated with the in vitro potency.

| S-EPMC8667308 | biostudies-literature

Discovery of Plasmodium vivax N-myristoyltransferase inhibitors: screening, synthesis, and structural characterization of their binding mode.

Project description:N-Myristoyltransferase (NMT) is a prospective drug target against parasitic protozoa. Herein we report the successful discovery of a series of Plasmodium vivax NMT inhibitors by high-throughput screening. A high-resolution crystal structure of the hit compound in complex with NMT was obtained, allowing understanding of its novel binding mode. A set of analogues was designed and tested to define the chemical groups relevant for activity and selectivity.

| S-EPMC3863987 | biostudies-literature

Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs.

Project description:The identification of a new series of P. falciparum growth inhibitors is described. Starting from a series of known human class I HDAC inhibitors a SAR exploration based on growth inhibitory activity in parasite and human cells-based assays led to the identification of compounds with submicromolar inhibition of P. falciparum growth (EC50 < 500 nM) and good selectivity over the activity of human HDAC in cells (up to >50-fold). Inhibition of parasital HDACs as the mechanism of action of this new class of selective growth inhibitors is supported by hyperacetylation studies.

| S-EPMC4867480 | biostudies-literature

Discovery of small molecule inhibitors of Plasmodium falciparum apicoplast DNA polymerase.

Project description:Malaria is caused by infection with protozoan parasites of the Plasmodium genus, which is part of the phylum Apicomplexa. Most organisms in this phylum contain a relic plastid called the apicoplast. The apicoplast genome is replicated by a single DNA polymerase (apPOL), which is an attractive target for anti-malarial drugs. We screened small-molecule libraries (206,504 compounds) using a fluorescence-based high-throughput DNA polymerase assay. Dose/response analysis and counter-screening identified 186 specific apPOL inhibitors. Toxicity screening against human HepaRG human cells removed 84 compounds and the remaining were subjected to parasite killing assays using chloroquine resistant P. falciparum parasites. Nine compounds were potent inhibitors of parasite growth and may serve as lead compounds in efforts to discover novel malaria drugs.

| S-EPMC9090415 | biostudies-literature

Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening.

Project description:In various malaria-endemic regions, the appearance of resistance has precluded the use of pyrimidine-based antifolate drugs. Here, a three-step fragment screening was used to identify new non-pyrimidine Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors. Starting from a 1163-fragment commercial library, a two-step differential scanning fluorimetry screen identified 75 primary fragment hits. Subsequent enzyme inhibition assay identified 11 fragments displaying IC50 in the 28-695 μM range and selectivity for PfDHFR. In addition to the known pyrimidine, three new anti-PfDHFR chemotypes were identified. Fragments from each chemotype were successfully co-crystallized with PfDHFR, revealing a binding in the active site, in the vicinity of catalytic residues, which was confirmed by molecular docking on all fragment hits. Finally, comparison with similar non-hit fragments provides preliminary input on available growth vectors for future drug development.

| S-EPMC8759724 | biostudies-literature

Molecules incorporating a benzothiazole core scaffold inhibit the N-myristoyltransferase of Plasmodium falciparum.

Project description:Recombinant N-myristoyltransferase of Plasmodium falciparum (termed PfNMT) has been used in the development of a SPA (scintillation proximity assay) suitable for automation and high-throughput screening of inhibitors against this enzyme. The ability to use the SPA has been facilitated by development of an expression and purification system which yields considerably improved quantities of soluble active recombinant PfNMT compared with previous studies. Specifically, yields of pure protein have been increased from 12 microg x l(-1) to >400 microg x l(-1) by use of a synthetic gene with codon usage optimized for expression in an Escherichia coli host. Preliminary small-scale 'piggyback' inhibitor studies using the SPA have identified a family of related molecules containing a core benzothiazole scaffold with IC50 values <50 microM, which demonstrate selectivity over human NMT1. Two of these compounds, when tested against cultured parasites in vitro, reduced parasitaemia by >80% at a concentration of 10 microM.

| S-EPMC2267354 | biostudies-literature