ABSTRACT
Analysis of Chemical Space “The critical and age-old question remains: how should a chemist decide what to synthesize?” (W.P. Walters, M.T. Stahl, M.A. Murcko)1
A main goal o f virtual screening is to select activity-enriched sets o f molecules - or single
molecules exhibiting desired activity-from the space o f all synthetically accessible
structures. Currently the most advanced H TS techniques allow for testing o f -TO5 compounds per day, and a typical corporate screening library contains several hundred thou-
sand samples. Although these facts alone represent a technological revolution, the turnover numbers still are extremely small compared with the total size o f chemical space.1 As a consequence, even ultra H TS combined with fast, parallel combinatorial chemistry can only be successful if a reasonable pre-selection o f molecules (or molecular building blocks) for screening is done. Otherwise this approach will more or less represent a random search with a very small probability o f success. While H TS and ultraHTS have made significant progress in recent years, we should bear in mind that it will be very costly to screen a million o f compounds
for activity in all the new receptor assays (estimated $0.1 to $10 per compound per screen). Even if a company has these resources, it is rare that they have access to a diverse one-million-
compound screening library. Thus it can be advantageous to integrate VS tools into the drug discovery process to find leads with novel scaffolds by either starting from competitor compounds described in the literature and/or from a proprietary, existing scaffold. Once a reliable VS process has been defined it can save resources and limit experimental efforts by suggesting defined sets o f molecules.
