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Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery

Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery

Published on: May 16, 2021

Discovery of YTHDF2 Ligands by Fragment-Based Design.

Annalisa Invernizzi¹, Francesco Nai¹, Rajiv Kumar Bedi¹

¹Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland.

ACS Bio & Med Chem Au

|August 27, 2025

Summary

Researchers identified new small molecules that bind to YTHDF2, a protein that recognizes N6-Adenosine methylation on mRNA. These compounds show potential for modulating m6A RNA pathways.

Keywords:

FRET binding assay docking epitranscriptomics m6A readers molecular dynamics protein crystallography

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Last Updated: Sep 10, 2025

Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery

Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery

Published on: May 16, 2021

Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source

Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source

Published on: May 29, 2021

NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode

NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode

Published on: June 4, 2021

Area of Science:

Biochemistry
Molecular Biology
Drug Discovery

Background:

N6-Adenosine methylation (m6A) is a prevalent mRNA modification.
YTH domain family proteins (YTHDF1-3) are key cytoplasmic readers of m6A.
Targeting m6A readers offers therapeutic potential.

Purpose of the Study:

To identify small molecule inhibitors of YTHDF2.
To characterize the binding affinity and selectivity of identified compounds.
To guide the optimization of m6A-binding ligands.

Main Methods:

Fragment-based drug discovery approach using molecular docking.
In vitro screening of a large fragment library against YTHDF2.
Structure-guided optimization and synthesis of analogues.
Biophysical assays including Fluorescence Polarization (FP) and Homogeneous Time-Resolved Fluorescence (HTRF).
X-ray crystallography of YTHDF2-ligand complexes.

Main Results:

Screening identified six initial active fragments from ~500,000 molecules.
Optimization yielded compounds with low-micromolar affinity for YTHDF2.
Compound 23 demonstrated high affinity (Kd=1.3 μM) and selectivity for YTHDF2.
Several compounds showed broad affinity for YTHDF1-3, with some binding YTHDC2.
Six crystal structures revealed YTHDF2-fragment complexes.

Conclusions:

Successful identification and optimization of YTHDF2-targeting small molecules.
Developed ligands with favorable ligand efficiency and low-micromolar affinity.
Demonstrated selectivity profiles against other YTH reader proteins.
Provided structural insights into YTHDF2-ligand interactions.