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

Combinatorial chemistry is a tool of increasing importance in the field of ligand design, as it can yield huge increases in the number of compounds available for screening. Unfortunately, it is often the case that the number of molecules which could theoretically be constructed greatly exceeds potential synthesis and screening capacity. For this new technology to be fully exploited, it will become vital to design libraries with reference to the properties of compounds already in existence, if the added value of each new molecular collection is truly to be maximized. Similarly, if we are to take full advantage of the potential of combinatorial chemistry in lead optimization, it is important that our library design paradigms are flexible, with diversity scoring functions that can be modified to suit particular projects. Here these challenges are addressed through the introduction of a novel computer-aided library design tool known as HARPick (heuristic algorithm for reagent picking). The program is accessible to the bench chemist, and incorporates several significant advances over currently available approaches. These include product-based diversity calculations that can be constrained at the reagent level; diversity measures constructed from multiple descriptors; improved pharmacophore key information and full pharmacophore profiling of entire molecular databases. The potential of these improvements to aid in diversity profiling is illustrated through comparison with established methodology, and possible further enhancements are discussed.