Complementary PLS and KNN algorithms for improved 3D-QSDAR consensus modeling of AhR binding

Multiple validation techniques (Y-scrambling, complete training/test set randomization, determination of the dependence of R(2)(test) on the number of randomization cycles, etc.) aimed to improve the reliability of the modeling process were utilized and their effect on the statistical parameters of the models was evaluated. A consensus partial least squares (PLS)-similarity based k-nearest neighbors (KNN) model utilizing 3D-SDAR (three dimensional spectral data-activity relationship) fingerprint descriptors for prediction of the log(1/EC(50)) values of a dataset of 94 aryl hydrocarbon receptor binders was developed. This consensus model was constructed from a PLS model utilizing 10 ppm x 10 ppm x 0.5 Å bins and 7 latent variables (R(2)(test) of 0.617), and a KNN model using 2 ppm x 2 ppm x 0.5 Å bins and 6 neighbors (R(2)(test) of 0.622). Compared to individual models, improvement in predictive performance of approximately 10.5% (R(2)(test) of 0.685) was observed. Further experiments indicated that this improvement is likely an outcome of the complementarity of the information contained in 3D-SDAR matrices of different granularity. For similarly sized data sets of Aryl hydrocarbon (AhR) binders the consensus KNN and PLS models compare favorably to earlier reports. The ability of 3D-QSDAR (three dimensional quantitative spectral data-activity relationship) to provide structural interpretation was illustrated by a projection of the most frequently occurring bins on the standard coordinate space, thus allowing identification of structural features related to toxicity.