Selective inhibition of the intermediate-conductance Ca(2+)-activated K(+ )channel (IK (Ca)) by some clotrimazole analogs has been successfully modeled using topological charge indexes (TCI) and genetic neural networks (GNNs). A neural network monitoring scheme evidenced a highly non-linear dependence between the IK (Ca) blocking activity and TCI descriptors. Suitable subsets of descriptors were selected by means of genetic algorithm. Bayesian regularization was implemented in the network training function with the aim of assuring good generalization qualities to the predictors. GNNs were able to yield a reliable predictor that explained about 97% data variance with good predictive ability. On the contrary, the best multivariate linear equation with descriptors selected by linear genetic search, only explained about 60%. In spite of when using the descriptors from the linear equations to train neural networks yielded higher fitted models, such networks were very unstable and had relative low predictive ability. However, the best GNN BRANN 2 had a Q ( 2 ) of LOO of cross-validation equal to 0.901 and at the same time exhibited outstanding stability when calculating 80 randomly constructed training/test sets partitions. Our model suggested that structural fragments of size three and seven have relevant influence on the inhibitory potency of the studied IK (Ca) channel blockers. Furthermore, inhibitors were well distributed regarding its activity levels in a Kohonen self-organizing map (KSOM) built using the inputs of the best neural network predictor.