New methodology for profiling combinatorial libraries and screening sets: cleaning up the design process with HARPick

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Combinatorial chemistry significantly increases compound numbers for screening in ligand design.
• The vast theoretical molecular space often exceeds practical synthesis and screening capacities.
• Effective library design requires considering existing compound properties and flexible paradigms for lead optimization.

Purpose of the Study:

• To introduce HARPick, a novel computer-aided library design tool.
• To address challenges in maximizing the value of combinatorial libraries and enabling flexible design paradigms.
• To improve diversity profiling and pharmacophore analysis in molecular databases.

Main Methods:

• Development of HARPick (heuristic algorithm for reagent picking), a user-friendly tool for bench chemists.
• Implementation of product-based diversity calculations constrained at the reagent level.
• Inclusion of multiple descriptor-based diversity measures and enhanced pharmacophore profiling.

Main Results:

• HARPick offers significant advances over existing approaches for library design.
• Demonstrated improvements in diversity profiling through comparative analysis.
• Facilitates better selection of compounds for screening and lead optimization.

Conclusions:

• HARPick enhances the exploitation of combinatorial chemistry in ligand design and lead optimization.
• The tool's flexibility and advanced features aid in maximizing the value of molecular collections.
• Further enhancements to HARPick hold potential for future library design methodologies.