Christian Lemmen

Virtual screening is widely established as part of the drug discovery process. So far, the primary domain of application are screening collections based on in-house repositories and vendor collections, while the pharma companies have access to large numbers of validated chemistries. It would be of great interest to perform similarity searches against all compounds that are synthetically accessible by any such combinatorial library protocol. However, the number of possible compounds easily exceeds – by many orders of magnitude – the number of compounds that can be stored and searched by conventional methods.

We overcame these limitations by converting large numbers of combinatorial libraries into a "virtual chemistry space". FTrees – a similarity calculator – is capable of searching such spaces without ever enumerating all possible molecular structures. It produces a set of compounds similar to a query structure, which are synthetically accessible via one or more of the existing synthetic routes. FTrees is known for its scaffold-hopping capabilities, thus chemically diverse results can be expected. Such output provides library design ideas for hit follow-up from high-throughput screening or lead hopping into novel series. A number of successful applications will be presented.