Mapping Functionally Relevant Tractable Lysines of Challenging Protein Targets by Covalent Fragment Screening

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Covalent fragment screening is a key strategy for identifying drug targets.
• Lysine residues are increasingly recognized for their potential in covalent labeling.
• Targeting challenging proteins requires innovative chemical approaches.

Purpose of the Study:

• To develop and characterize a novel lysine-targeting covalent fragment library.
• To screen this library against therapeutically relevant protein targets.
• To explore the potential of lysine-targeting covalent chemistry in drug discovery.

Main Methods:

• Systematic characterization of reactivity and stability for library members.
• Screening of the lysine-targeting covalent fragment library against protein targets.
• Characterization of binding sites using enzymatic digestion and computational modeling.

Main Results:

• A diverse library of lysine-targeting covalent fragments was synthesized and validated.
• The library successfully identified suitable covalent warheads against challenging protein targets.
• Binding sites were characterized, demonstrating the utility of this approach.

Conclusions:

• Lysine-targeting covalent chemistry is a powerful strategy for expanding binding site discovery.
• This approach supports warhead optimization for diverse protein targets.
• The developed library offers significant potential for medicinal chemistry and chemical biology applications.