ArticleACS chemical biology2018
Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as "Doorstop" for NADPH Entry.
Article in ACS chemical biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 35 citations in OpenAlex.
- Crystal structure of Mycobacterium tuberculosis mycothione reductase in complex with a specific inhibitor reveals competition with NADP(H) binding.FEBS letters · 2026Article
- Synthesis of Methoxylated Benzoxanthones as Drug Metabolites of Antischistosomal Schistodiones-A Limited Environmental Risk.Molecules (Basel, Switzerland) · 2026Article
- Synthesis of novel biologically active pyridonaphthyridine derivatives by employing FeRSC advances · 2025Article
- Novel Antischistosomal Drug Targets: Identification of Alkaloid Inhibitors of SmTGR via Integrated In Silico Methods.Pathogens (Basel, Switzerland) · 2025Article
- Article
- Green synthesis and cytotoxic activity of functionalized naphthyridine.Molecular diversity · 2025Article
- Pleiotropic anti-cancer activities of novel non-covalent thioredoxin reductase inhibitors against triple negative breast cancer.Free radical biology & medicine · 2025Article
- The "Doorstop Pocket" In Thioredoxin Reductases─An Unexpected Druggable Regulator of the Catalytic Machinery.Journal of medicinal chemistry · 2024Review
- Fragment library screening by X-ray crystallography and binding site analysis on thioredoxin glutathione reductase of Schistosoma mansoni.Scientific reports · 2024Article
- Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo.Nature communications · 2023Article
- Assigning function to active site residues ofFrontiers in molecular biosciences · 2023Article
- A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis.Pharmaceutics · 2022Article
- Biochemical and structural characterizations of thioredoxin reductase selenoproteins of the parasitic filarial nematodes Brugia malayi and Onchocerca volvulus.Redox biology · 2022Article
- First In Silico Screening of Insect Molecules for Identification of Novel Anti-Parasitic Compounds.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Computer-Assisted Discovery of Alkaloids with Schistosomicidal Activity.Current issues in molecular biology · 2022Article
- Innovative Approach for a Classic Target: Fragment Screening on Trypanothione Reductase Reveals New Opportunities for Drug Design.Frontiers in molecular biosciences · 2022Article
- Gram-Scale Synthesis of 1,8-Naphthyridines in Water: The Friedlander Reaction Revisited.ACS omega · 2021Article
- Probing the Surface of a Parasite Drug Target Thioredoxin Glutathione Reductase Using Small Molecule Fragments.ACS infectious diseases · 2021Article
- Taking Advantage of the Morpheein Behavior of Peroxiredoxin in Bionanotechnology.Bioconjugate chemistry · 2021Review
- Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence.Frontiers in immunology · 2021Review
Corrections and comments
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Authors and funding
17 authors at 7 institutions in 4 countries.
Funding
Abstract
Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off-target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectively inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms, the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases.
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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.