Generating libraries of small molecules that possess a high degree of structural diversity is important for maximizing the chances of finding active compounds in screening programmes. A frequently used method for creating molecular diversity is to attach a large number of different building blocks to a common molecular skeleton, which can be efficiently achieved using established combinatorial chemistry approaches. But although these building blocks can be highly diverse, the way in which they are displayed in three-dimensional space — and therefore their potential to be complementary to the three-dimensional surface of a protein target — is limited by the fact that the molecules share the same skeleton. So, what is needed to address this issue are ways to efficiently generate diversity in molecular skeletons. Stuart Schreiber and colleagues now describe just such a strategy in the 24 October issue of Science.

The key to highly efficient generation of diversity in attached building blocks is a technique known as split–pool synthesis. This combinatorial chemistry approach, in which multiple substrates are transformed simultaneously under a common set of reaction conditions, can produce all possible combinations of a given set of building blocks attached to a common skeleton in the fewest steps. To achieve an analogous goal with molecular skeletons, the authors identified 'skeletal information elements' — sets of appendages on a special latently reactive common skeleton that react with the skeleton itself under a common set of conditions to give defined products with different skeletons.

The authors then demonstrated the potential of their combinatorial skeletal-diversity strategy in tandem with conventional combinatorial building-block variation using split–pool synthesis. A 1,260-compound library representing all possible combinations of six skeletons, derivatized at two separate sites with seven and fifteen different building blocks, respectively, in both enantiomeric and diastereomeric forms (6 × 7 × 15 × 2 = 1,260) was produced in just five steps. The next step is systematic biological screening of this library to clarify the role of the three diversity elements — skeletal, building-block and stereochemical — in small-molecule–protein interactions. It will be interesting to see how the hit rate is influenced by the skeletal diversity in particular.