Structure-based identification of the first 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. Herein we present the first 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, C55. The identified compound, already proved to be free from potential ADMET concerns, inhibits TrxR1 in a dose-dependent manner, with an IC50 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 the first metal-free organic molecule capable of non-covalently inhibiting TrxR1, C55 represents a significant breakthrough, offering a solid foundation for hit-to-lead optimization and the development of new anticancer drug candidates.