Covalent fragment libraries in drug discovery.

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Targeted covalent inhibitors and chemical probes are essential in modern drug discovery.
• Fragment-based drug discovery (FBDD) offers advantages for identifying novel therapeutic strategies.
• Electrophilic fragments present a promising avenue for targeting difficult proteins.

Purpose of the Study:

• To review principles and considerations for designing electrophilic fragment libraries.
• To summarize screening methodologies for covalent fragments.
• To highlight drug discovery applications utilizing covalent fragment libraries.

Main Methods:

• Library design: Selection of covalent warheads and fragment design.
• Screening methodologies: Assays against surrogate models, proteins, and whole proteomes or cells.
• Application review: Case studies of covalent fragment library use in drug discovery.

Main Results:

• Established principles for designing effective electrophilic fragment libraries.
• Detailed overview of diverse screening approaches for covalent fragments.
• Demonstrated success of covalent fragment libraries in advancing drug discovery projects.

Conclusions:

• Electrophilic fragment screening is a viable and powerful strategy for drug discovery.
• This approach facilitates the identification and validation of novel drug targets.
• Covalent fragment libraries provide valuable starting points for developing therapeutics, especially for challenging targets.