The TOPological Sub-Structural Molecular Design (TOPS-MODE) approach has been applied to the study of the permeability coefficient of various compounds through low-density polyethylene at 21.1degreesC. A model able to describe closed to 90% of the variance in the experimental permeability of 63 organic compounds was developed with the use of the mentioned approach. In contrast, no one of nine different approaches, including the use of constitutional, topological, BCUT, 2D autocorrelations, geometrical, RDF, 3D Morse, WHIM and GETAWAY descriptors was able to explain more than 73% of the variance in the mentioned property with the same number of descriptors. In addition, genetic algorithms were used in feature selection experiments considering all molecular descriptors in order to obtain mixed models. Although, statistically significant models were derived containing other descriptors than spectral moments still the best one fitted out model was find with these variables. Finally, the TOPS-MODE approach permitted to find the contribution of different fragments to the permeability coefficients giving to the model a straightforward structural interpretability. (C) 2003 Published by Elsevier Ltd.