Why the study?
Pyridine nucleotide-disulfide oxidoreductases are underexplored as drug targets, and selective thioredoxin reductase inhibition remains challenging primarily due to reliance on covalent inhibition strategies.
The discovery of the 'doorstop pocket' in thioredoxin reductases provides a novel druggable site for developing therapies against schistosomiasis, cancer, and infectious diseases.
Novel doorstop pocket enables non-covalent TrxR inhibition; leaves open translation to schistosomiasis therapies.
Pyridine nucleotide-disulfide oxidoreductases are underexplored as drug targets, and thioredoxin reductases (TrxRs) stand out as compelling pharmacological targets. Selective TrxR inhibition is challenging primarily due to the reliance on covalent inhibition strategies. Recent studies identified a regulatory and druggable pocket in Schistosoma mansoni thioredoxin glutathione reductase (TGR), a TrxR-like enzyme, and an established drug target for schistosomiasis. This site is termed the “doorstop pocket” because compounds that bind there impede the movement of an aromatic side-chain necessary for the entry and exit of NADPH and NADP + during enzymatic turnover. This discovery spearheaded the development of new TGR inhibitors with efficacies surpassing those of current schistosomiasis treatment. Targeting the “doorstop pocket” is a promising strategy, as the pocket is present in all members of the pyridine nucleotide-disulfide oxidoreductase family, opening new avenues for exploring therapeutic approaches in diseases where the importance of these enzymes is established, including cancer and inflammatory and infectious diseases.
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Ardini et al. (2024) studied this question.
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