Scaffold-Based Libraries Versus Make-on-Demand Space: A Comparative Assessment of Chemical Content

Area of Science:

• Medicinal Chemistry
• Chemoinformatics
• Drug Discovery

Background:

• Chemical libraries are crucial for high-throughput screening in drug discovery.
• Two libraries were previously developed: eIMS (in-stock compounds) and vIMS (virtual compounds).
• vIMS was derived from eIMS scaffolds and decorated with custom R-groups.

Purpose of the Study:

• To validate a scaffold-based library design approach.
• To compare its effectiveness against reaction- and building block-based methods.
• To assess the value of scaffold-based design for lead optimization.

Main Methods:

• Developed two scaffold-focused datasets using the Enamine REAL Space library.
• Systematically compared scaffold-focused datasets with make-on-demand chemical space.
• Performed synthetic accessibility analysis on compound sets.

Main Results:

• Scaffold-based and make-on-demand libraries showed similarity with limited overlap.
• A significant portion of R-groups in the scaffold-based library were not identified in the make-on-demand library.
• Compound sets exhibited low to moderate synthetic difficulty.

Conclusions:

• The scaffold-based method is valuable for generating focused chemical libraries.
• This approach offers high potential for lead optimization in drug discovery.
• Scaffold-based design complements traditional library generation methods.