Design of Array-Type Compound Libraries that Combine Information from Natural Products and Synthetic Molecules

A new approach to the design of compound libraries, named MetaFocus (Metabolite-Focused library), is presented that exploits information encoded in natural molecules and combines naturally occurring and synthetic compounds. An important goal of the MF approach is the identification of synthetic compounds that mimic properties of natural molecules that are difficult to obtain in sufficient quantities or to synthesize. Compounds in MetaFocus (MF) arrays are focused on natural molecules with attractive therapeutic effects. Similarity search and diversity design techniques are employed to generate compound arrays that start from a selected natural molecule, add similar molecules, either from natural or synthetic sources, and diversify scaffolds derived from these molecules. Since the identification of similar molecules from natural and synthetic sources plays a significant role in our library design efforts, the performance of fingerprint-type search tools was systematically assessed in a newly assembled test database consisting of 16 biological activity classes. MF arrays are organized as an easily expandable and searchable data structure and serve as a knowledge base for drug discovery applications. Here we introduce the design principles and organization of MF arrays and present example applications.