ArticleDrug design, development and therapy2026
Characterization of the Second-Generation Covalent Fragment Library (CovLib Gen2): Thiol Reactivity Profiling and p53-Y220C Rescue.
Article in Drug design, development and therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- A Perspective on Covalent Hit Identification and Validation in the European Pharmaceutical Industry.Chembiochem : a European journal of chemical biology · 2026Article
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7 authors.
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Abstract
Purpose: Covalent Fragment-Based Drug Discovery (FBDD) has emerged as a powerful strategy for unlocking challenging pharmacological targets and engaging shallow or "cryptic" binding pockets. In this study, we present the design and characterization of the Second Generation Covalent Fragment Library (CovLib Gen2), an expanded collection of 81 structurally diverse electrophiles tailored for Covalent Fragment-Based Drug Discovery (FBDD) using an electrophile-first approach. The library spans five distinct warhead classes, including epoxides, vinyl sulfones, acrylamides, α-cyanoacrylamides, and a core set of SɴAr-reactive heteroarenes. Methods: We comprehensively profiled the library for physicochemical properties and intrinsic thiol reactivity using high-throughput 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) and high-performance liquid chromatography (HPLC)-based glutathione (GSH) reactivity assays. To demonstrate the library's utility, we performed differential scanning fluorimetry (DSF) screening against the oncogenic, thermally unstable p53-Y220C mutant and subsequent specificity testing with two control mutants. Results: The library exhibited a broad dynamic range of reactivities with a clear correlation between the assay methods. Additionally, we identified 12 fragments with desirable mild reactivity profiles (t Conclusion: Our findings validate CovLib Gen2 as a versatile tool for ligand discovery, including electrophilic fragments covering a broad range of reactivity, and provide tractable starting points for the pharmacological rescue of p53-Y220C.
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