On sampling of fragment space

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Chemistry

Background:

• Fragment-based lead discovery (FBLD) is a key strategy in drug discovery, complementing traditional high-throughput screening (HTS).
• Various FBLD screening techniques exist for libraries of 10^3–10^4 fragments.
• Assessing the practical success rates of FBLD is crucial for optimizing lead generation.

Purpose of the Study:

• To investigate the practical success rates of fragment-like libraries in lead discovery.
• To evaluate the potential for identifying potent hits using accessible compound sets.
• To compare FBLD success rates with commonly used HTS protocols.

Main Methods:

• Interrogating medicinal chemistry databases for multiple drug discovery programs.
• Creating virtual libraries from commercially available reagents and fragments.
• Analyzing screening results under conditions similar to HTS protocols.

Main Results:

• Potent hits, exceeding those typically found in current FBLD screens, can be consistently identified.
• Realistically accessible compound sets demonstrate high success rates in FBLD.
• HTS-like screening conditions are effective for fragment library screening.

Conclusions:

• Fragment-based lead discovery is a viable and effective strategy for identifying potent drug leads.
• Accessible fragment libraries, when screened under appropriate conditions, yield significant results.
• FBLD offers a practical and successful alternative to traditional HTS for lead generation.