Enriching screening libraries with bioactive fragment space.

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Bioactive molecules are crucial for drug discovery.
• Existing screening libraries often underrepresent key ring systems.
• Fragment-based drug discovery requires libraries with high coverage and enrichment of bioactive scaffolds.

Purpose of the Study:

• To identify and characterize bioactive ring systems within a large molecule library.
• To assess the overlap of these ring systems with commercial compound collections.
• To propose a strategy for building improved virtual fragment libraries.

Main Methods:

• Deconvolution of 238,073 bioactive molecules into extended Murcko ring systems.
• Clustering of ring systems using ECFP4 fingerprints (ECFP4).
• Quantification of overlap with commercial libraries and assessment of molecular complexity.

Main Results:

• Identified 2245 prevalent ring systems, clustered into 2221 groups.
• Demonstrated that small fragment library success depends on coverage, enrichment, and low complexity.
• Found significant underrepresentation of bioactive ring systems in current screening libraries.

Conclusions:

• A virtual fragment library, derived from bioactive molecules, can enhance screening library coverage.
• This approach aids in discovering novel inhibitors, as shown by the identification of protein kinase CK2 inhibitors with potent activity (IC50 = 0.5μM).
• The proposed strategy optimizes fragment library design for effective drug discovery.