Prediction of telomerase inhibitory activity for acridinic derivatives based on chemical structure

Telomerase is a reverse transcriptase enzyme that activates in more than 85% of cancer cells and it is associated with the acquisition of a malignant phenotype. Some experimental strategies have been suggested in order to avoid the enzyme effect on unstopped telomere elongation. One of them, the stabilization of the G-quartet structure, has been widely studied. Nevertheless, no QSAR studies to predict this activity have been developed. In the present study a classification model was carried out to identify, through molecular descriptors with structural fragments and groups information, those acridinic derivatives with better inhibitory concentration on telomerase enzyme. A linear discriminant model was developed to classify a data set of 90 acridinic derivatives (48 more potent derivatives with IC50 < 1 mu M and 42 less potent with IC50 >= 1 mu M). The final model fit the data with sensitivity of 87.50% and specificity of 82.85%, for a final accuracy of 85.33%. The predictive ability of the model was assessed by a prediction set (15 compounds of 90% and 82.29% of prediction accuracy); a tenfold full cross-validation procedure (removing 15 compounds in each cycle, 84.80% of good prediction) and the prediction of inhibitory concentration on telomerase enzyme for external data of 10 novel acridines (90% of good prediction). The results of this study suggest that the established model has a strong predictive ability and can be prospectively used in the molecular design and action mechanism analysis of this kind of compounds with anticancer activity. (C) 2009 Elsevier Masson SAS. All rights reserved.