Predicting kinase selectivity profiles using Free-Wilson QSAR analysis

Kinases are involved in a variety of diseases such as cancer, diabetes, and arthritis. In recent years, many kinase small molecule inhibitors have been developed as potential disease treatments. Despite the recent advances, selectivity remains one of the most challenging aspects in kinase inhibitor design. To interrogate kinase selectivity, a panel of 45 kinase assays has been developed in-house at Pfizer. Here we present an application of in silico quantitative structure activity relationship (QSAR) models to extract rules from this experimental screening data and make reliable selectivity profile predictions for all compounds enumerated from virtual libraries. We also propose the construction of R-group selectivity profiles by deriving their activity contribution against each kinase using QSAR models. Such selectivity profiles can be used to provide better understanding of subtle structure selectivity relationships during kinase inhibitor design.