The importance of the domain of applicability in QSAR modeling

The domain of applicability is an important concept in quantitative structure activity relationships (QSAR) that allows one to estimate the uncertainty in the prediction of a particular molecule based on how similar it is to the compounds used to build the model. In this paper we discuss this important concept, providing details of the development and application of a method to compute the domain of applicability within model descriptor space and structural space as defined by daylight fingerprints. The importance of the domain of applicability is illustrated using five QSAR models generated on plasma protein binding and P450 inhibition datasets. Such methodologies will be shown to offer us a means to monitor the performance of QSARs over time, providing us both with a way to estimate the accuracy of a given prediction and identify when a model needs to be rebuilt. (C) 2008 Elsevier Inc. All rights reserved.