Structure-based identification of a non-covalent thioredoxin reductase inhibitor with proven ADMET suitability

Thioredoxin reductase 1 (TrxR1), a selenoprotein enzyme crucial for redox homeostasis in mammals, has emerged as a promising target for anticancer therapy. In this study, we present a non-covalent TrxR1 inhibitor, identified through an integrated experimental and computational approach. After identifying a plausible druggable cavity, a molecular docking-based virtual screening of over 90,000 lead-like compounds was performed. The selected compounds were evaluated for their impact on TrxR1 activity, leading to the identification of the most promising candidate, <b>C55</b>. The identified compound, already proven to be free from potential ADMET concerns, inhibits TrxR1 in a dose-dependent manner, with an IC<sub>50</sub> value in the micromolar range. C55's activity was confirmed across multiple cancer cell lines, including HepG2, Huh7, MCF-7, and MDA-MB-231 cells. As a metal-free organic molecule capable of non-covalently inhibiting TrxR1, C55 represents a significant breakthrough, offering a solid foundation for hit-to-lead optimisation and the development of new anticancer drug candidates.

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Publication Details

Journal
Journal of Enzyme Inhibition and Medicinal Chemistry
Published
2025-11-10
DOI
https://doi.org/10.1080/14756366.2025.2585606
Primary Topic
Redox biology and oxidative stress
Type
article
Field-Weighted Citation Impact
0.00

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article

Structure-based identification of a non-covalent thioredoxin reductase inhibitor with proven ADMET suitability

Giuseppe Felice Mangiatordi, Luisa Ronga, Michele Saviano, Ilaria Silvestri et al.
Journal of Enzyme Inhibition and Medicinal Chemistry
Redox biology and oxidative stress
article

Structure-based identification of a non-covalent thioredoxin reductase inhibitor with proven ADMET suitability

Giuseppe Felice Mangiatordi, Luisa Ronga, Michele Saviano, Ilaria Silvestri, Antonina Azzolina, Giuseppa Augello, G. Lamanna, Diego Tesauro, Melchiorre Cervello
article en

Abstract

Thioredoxin reductase 1 (TrxR1), a selenoprotein enzyme crucial for redox homeostasis in mammals, has emerged as a promising target for anticancer therapy. In this study, we present a non-covalent TrxR1 inhibitor, identified through an integrated experimental and computational approach. After identifying a plausible druggable cavity, a molecular docking-based virtual screening of over 90,000 lead-like compounds was performed. The selected compounds were evaluated for their impact on TrxR1 activity, leading to the identification of the most promising candidate, <b>C55</b>. The identified compound, already proven to be free from potential ADMET concerns, inhibits TrxR1 in a dose-dependent manner, with an IC<sub>50</sub> value in the micromolar range. C55's activity was confirmed across multiple cancer cell lines, including HepG2, Huh7, MCF-7, and MDA-MB-231 cells. As a metal-free organic molecule capable of non-covalently inhibiting TrxR1, C55 represents a significant breakthrough, offering a solid foundation for hit-to-lead optimisation and the development of new anticancer drug candidates.

Journal of Enzyme Inhibition and Medicinal ChemistryVol. 40(1)
Université de Pau et des Pays de l'Adour (FR), National Academies of Sciences, Engineering, and Medicine (US), Institut des Sciences Analytiques et de Physico-Chimie pour l'Environnement et les Matériaux (FR), National Research Council (RO), Institute for Biomedical Research and Innovation (IT), National Research Council (IT), Centro Interuniversitario di Ricerca sui Peptidi Bioattivi (IT), Institute of Crystallography (IT), University of Bari Aldo Moro (IT), University of Naples Federico II (IT)
European Commission, Ligue Contre le Cancer
Openalex Percentile: Top 70%
Redox biology and oxidative stress
DOIOpen Access PDFOpenAlex
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