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 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 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.