Accurate prediction of the blood-brain partitioning of a large set of solutes using ab initio calculations and genetic neural network modeling

A genetic algorithm‐based artificial neural network model has been developed for the accurate prediction of the blood–brain barrier partitioning (in logBB scale) of chemicals. A data set of 123 logBB (115 old molecules and 8 new molecules) of a diverse set of chemicals was chosen in this study. The optimum 3D geometry of the molecules was estimated by the ab initio calculations at the level of RHF/STO‐3G, and consequently, different electronic descriptors were calculated for each molecule. Indeed, logP as a measure of hydrophobicity and different topological indices were also calculated. A three‐layered artificial neural network with backpropagation of an error‐learning algorithm was employed to process the nonlinear relationship between the calculated descriptors and logBB data. Genetic algorithm was used as a feature selection method to select the most relevant set of descriptors as the input of the network. Modeling of the logBB data by the only quantum descriptors produced a 5:4:1 ANN structure with RMS error of validation and crossvalidation equal to 0.224 and 0.227, respectively. Better nonlinear model (RMSV and RMSCV equals to 0.097 and 0.099, respectively) was obtained by the incorporation of the logP and the principal components of the topological indices to electronic descriptors. The ultimate performances of the models were obtained by the application of the models to predict the logBB of 23 molecules that did not have contribution in the steps of model development. The best model produced RMS error of prediction 0.140, and could predict about 98% of variances in the logBB data. © 2006 Wiley Periodicals, Inc. J Comput Chem 27: 1125–1135, 2006