Telomerase Inhibitory Activity of Acridinic Derivatives: A 3D-QSAR Approach

摘要

Telomerase is a reverse transcriptase enzyme that activates in more than 85% of cane cells and it associated with the acquisition of a malignant phenotype. Some experimei strategies have been suggested in order to avoid the enzyme effect on unstopped telo 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, the present study, several regression models were developed to identify, through 3-D molecular descriptors, those acridinic derivatives with better inhibitory activity on the telomerase enzyme (log ~(tel)EC_(50)). Linear regression models were developed from a dataset of 85 acridinic derivatives and the best results were achieved using GETAWAY and WHIM molecular descriptors. The final model explained 80% of the variance and the predictive ability was assessed by a leave-one-out cross-validation (Q~2_(LOO))=743), a prediction set (21 compounds of the 85; R~2_(pred) =71.50 and SDEP_(pred) = 0.366), and the prediction of inhibitory activity on telomerase enzyme for external set of ten novel acridines. 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.