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Related Concept Videos

In vitro Mutagenesis01:16

In vitro Mutagenesis

To learn more about the function of a gene, researchers can observe what happens when the gene is inactivated or “knocked out,” by creating genetically engineered knockout animals. Knockout mice have been particularly useful as models for human diseases such as cancer, Parkinson’s disease, and diabetes.
In-vitro Mutagenesis01:16

In-vitro Mutagenesis

To learn more about the function of a gene, researchers can observe what happens when the gene is inactivated or “knocked out,” by creating genetically engineered knockout animals. Knockout mice have been particularly useful as models for human diseases such as cancer, Parkinson’s disease, and diabetes.

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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Characterization of the Second-Generation Covalent Fragment Library (CovLib Gen2): Thiol Reactivity Profiling and

Martin Schwer1, Sven R Aldea1, Marc U Engelhardt1

  • 1Department of Pharmacy and Biochemistry, Laboratory for Molecular Design & Pharmaceutical Biophysics, Eberhard Karls Universität Tübingen, Institute of Pharmaceutical Sciences, Tübingen, 72076, Germany.

Drug Design, Development and Therapy
|May 25, 2026
PubMed
Summary
This summary is machine-generated.

The Second Generation Covalent Fragment Library (CovLib Gen2) offers diverse electrophilic fragments for drug discovery. This library successfully identified novel stabilizers for the p53-Y220C mutant, advancing covalent fragment-based drug discovery.

Keywords:
55’-dithiobis-(2-nitrobenzoic acid)covalent fragment-based drug discoverydifferential scanning fluorimetryglutathionetumor suppressor p53warheads

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Covalent Fragment-Based Drug Discovery (FBDD) is crucial for targeting difficult proteins.
  • Shallow or cryptic binding pockets present significant challenges in drug development.
  • Electrophile-first approaches are vital for designing covalent inhibitors.

Purpose of the Study:

  • To introduce and characterize the Second Generation Covalent Fragment Library (CovLib Gen2).
  • To expand the toolkit for Covalent Fragment-Based Drug Discovery (FBDD) with diverse electrophiles.
  • To provide starting points for targeting challenging protein targets like p53-Y220C.

Main Methods:

  • Profiling physicochemical properties and thiol reactivity of the CovLib Gen2 library.
  • Utilizing high-throughput DTNB and HPLC-based GSH reactivity assays.
  • Employing differential scanning fluorimetry (DSF) for screening against p53-Y220C and control mutants.

Main Results:

  • The library demonstrated a wide reactivity range, correlating well between assay methods.
  • 12 fragments showed desirable mild reactivity profiles (t½GSH = 1-10 h).
  • DSF screening identified 15 hits, with SN054 being the most potent p53-Y220C stabilizer (4.5 °C shift) and showing specificity.

Conclusions:

  • CovLib Gen2 is a validated, versatile tool for electrophilic fragment discovery.
  • The library provides tractable starting points for covalent ligand development.
  • The findings facilitate the pharmacological rescue of the p53-Y220C mutant.