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 fiel d of ligand design, as it can yield huge increases in the number of co mpounds available for screening. Unfortunately, it is often the-case t hat the number of molecules which could theoretically be constructed g reatly exceeds potential synthesis and screening capacity. For this ne w technology to be fully exploited, it will become vital to design lib raries with reference to the properties of compounds already in existe nce, if the added value of each new molecular collection is truly to b e maximized. Similarly, if we are to take full advantage of the potent ial of combinatorial chemistry in lead optimization, it is important t hat 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 r eagent picking). The program is accessible to the bench chemist, and i ncorporates several significant advances over currently available appr oaches. 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 thr ough comparison with established methodology, and possible further enh ancements are discussed.