Fragment-based covalent ligand discovery.

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Targeted covalent inhibitors are gaining prominence in drug discovery and biomedical research.
• Advances in mass spectrometry and chemoproteomics have identified numerous protein targets for covalent modification.
• Fragment-based drug discovery (FBDD) is now applied at a proteome-wide scale.

Purpose of the Study:

• To review the emerging field of covalent fragment-based ligand discovery (CFBLD).
• To highlight the synergy between covalent targeting and FBDD.
• To discuss the potential of CFBLD in identifying modulators for new and established therapeutic targets.

Main Methods:

• Integration of covalent targeting strategies with fragment-based medicinal chemistry.
• Utilizing chemoproteomic approaches for proteome-wide screening.
• Development of novel reactive chemistries targeting amino acid residues beyond cysteine (e.g., lysine, tyrosine).

Main Results:

• CFBLD facilitates the discovery of novel covalent ligands and their protein targets.
• This approach enables high-throughput identification of cryptic pockets.
• It leads to the discovery of modulators for proteins previously considered undruggable.

Conclusions:

• Covalent fragment-based ligand discovery offers a powerful and efficient method for identifying new pharmacological modulators.
• The integration of covalent chemistry and FBDD expands the druggable proteome.
• This strategy holds significant promise for developing therapeutics against challenging disease targets.