QSAR studies about cytotoxicity of benzophenazines with dual inhibition toward both topoisomerases I and II: 3D-MoRSE descriptors and statistical considerations about variable selection

Abstract

Deoxyribonucleic acid (DNA) topoisomerases are involved in diverse cellular processes, such as replication, transcription, recombination, and chromosome segregation. Searching new compounds that inhibit both topoisomerases I and II is very important due to the deficiency of the specific inhibitors to overcome multidrug resistance (MDR). A QSAR study was developed, employing the 3D-MoRSE descriptors and a set of 64 benzophenazines in order to model the inhibition of the topoisomerases I and II, expressed by the cytotoxicity of these compounds (IC 50) versus drug-resistant human small cell lung carcinoma line cell H69/LX4. A comparison with other approaches such as the Topological, BCUT, Galvez topological charge indexes, 2D autocorrelations, Randić molecular profile, Geometrical, RDF, and WHIM descriptors was carried out. The mathematical models were obtained by means of the multiple regression analysis (MRA) and the variables were selected using the genetic algorithm. The model relative to the 3D-MoRSE descriptors was considered as the best, taking into account its statistical parameters. It was able to describe more than 82.2% of the variance in the experimental activity once the outliers were extracted.