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ACS Chem Biol. 2018 Aug 17;13(8):2190-2202. doi: 10.1021/acschembio.8b00349. Epub 2018 Jun 11.

Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as "Doorstop" for NADPH Entry.

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Department of Life, Health and Environmental Sciences , University of L'Aquila , 67100 L'Aquila , Italy.
Department of Microbial Pathogens and Immunity , Rush University Medical Center , Chicago , Illinois 60612 , United States.
Department of Biochemical Sciences , Sapienza University of Rome , 00185 Roma , Italy.
UMR5246 ICBMS - CNRS - UCBL , Université de Lyon , 69007 Lyon , France.
National Center for Advancing Translational Sciences, National Institutes of Health , Bethesda , Maryland 20892 , United States.
Department of Medical Biochemistry and Biophysics , Karolinska Institutet , SE-171 77 Stockholm , Sweden.
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , University of Illinois at Chicago , Chicago , Illinois 60607 , United States.


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.

[Indexed for MEDLINE]

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