QSAR Applicability Domain Estimation by Projection of the Training Set in Descriptor Space: A Review

Abstract

As the use of Quantitative Structure Activity Relationship (QSAR) models for chemical management increases, the reliability of the predictions from such models is a matter of growing concern. The OECD QSAR Validation Principles recommend that a model should be used within its applicability domain (AD). The Setubal Workshop report provided conceptual guidance on defining a (Q)SAR AD, but it is difficult to use directly. The practical application of the AD concept requires an operational definition that permits the design of an automatic (computerised), quantitative procedure to determine a model's AD. An attempt is made to address this need, and methods and criteria for estimating AD through training set interpolation in descriptor space are reviewed. It is proposed that response space should be included in the training set representation. Thus, training set chemicals are points in n-dimensional descriptor space and m-dimensional model response space. Four major approaches for estimating interpolation regions in a multivariate space are reviewed and compared: range, distance, geometrical, and probability density distribution.