Introducing the metacore concept for multi-target ligand design.

In this work, we introduce the concept of "metacores" (MCs) for the organization of analog series (ASs) and multi-target (MT) ligand design. Generating compounds that are active against distantly related or unrelated targets is a central task in polypharmacology-oriented drug discovery. MCs are obtained by two-stage extraction of structural cores from ASs. The methodology is chemically intuitive and generally applicable. Each MC represents a set of related ASs and a template for the generation of new structures. We have systematically identified ASs that exclusively consisted of analogs with MT activity and determined their target profiles. From these ASs, a large set of 317 structurally diverse MCs was extracted, 127 of which were associated with different target families. The newly generated MCs were characterized and further prioritized on the basis of AS, compound, and target coverage. The analysis indicated that 260 MCs were pharmaceutically relevant. These MCs and the compound and target information they capture are made freely available for medicinal chemistry applications.