Covalent hits and where to find them

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Covalent inhibitors are increasingly important in drug discovery.
• Electrophile-first screening campaigns offer a viable strategy for identifying covalent hits.
• Successful implementation requires adherence to best practices.

Purpose of the Study:

• To review the current state-of-the-art in covalent hit identification.
• To outline methods for identifying hits from covalent libraries.
• To provide guidance on selecting compounds for medicinal chemistry programs.

Main Methods:

• Electrophile-first screening campaigns.
• Biophysical and biochemical assays.
• Cellular approaches.
• DNA-encoded libraries.

Main Results:

• Covalent hits can be routinely identified using established screening techniques.
• A systematic approach is crucial for successful covalent hit identification.
• Selection criteria are vital for advancing covalent compounds into medicinal chemistry programs.

Conclusions:

• Covalent hit identification is a practical approach in modern drug discovery.
• Utilizing a combination of screening methods enhances hit identification.
• Careful compound selection is essential for successful covalent drug development.