Application of FreeWilson Selectivity Analysis for Combinatorial Library Design

In this chapter we present an application of in silico quantitative structure–activity relationship (QSAR) models to establish a new ligand-based computational approach for generating virtual libraries. The Free–Wilson methodology was applied to extract rules from two data sets containing compounds which were screened against either kinase or PDE gene family panels. The rules were used to make predictions for all compounds enumerated from their respective virtual libraries. We also demonstrate the construction of R-group selectivity profiles by deriving activity contributions against each protein target using the QSAR models. Such selectivity profiles were used together with protein structural information from X-ray data to provide a better understanding of the subtle selectivity relationships between kinase and PDE family members.