GQSAR modeling and combinatorial library generation of 4-phenylquinazoline-2-carboxamide derivatives as antiproliferative agents in human Glioblastoma tumors

Abstract

BackgroundTSPO translocator protein, encoded in humans by the Tspo gene plays a crucial role in mitochondria mediated apoptosis and necrotic cell death through its association with Mitochondrial Permeability Transition pore (MPTP). It has been shown that this function can be exploited as a potential treatment for human Glioblastoma Multiforme. In this study, a novel robust fragment based QSAR model has been developed for a series of 4-phenylquinazoline-2-carboxamides experimentally known to be ligands for TSPO, thus triggering apoptotic mechanism cascade. ResultsModel developed showed satisfactory statistical parameters for the experimentally reported dataset (r2=0.8259, q2=0.6788, pred_r2=0.8237 and F-test=37.9). Low standard error values (r2_se=0.253, q2_se=0.34, pred_r2_se=0.14) confirmed the accuracy of the generated model. The model obtained had 4 descriptors, namely, R1-Volume, R2-SsCH3E-index, R3-SsCH3count and R5-EpsilonR. Two of them had positive contribution while the other two had negative correlation. ConclusionThe high binding affinity and the presence of essential structural features in these compounds make them an ideal choice for the consideration as potent anti-GBM drugs. Activity predicted by GQSAR model reinforces their potential as worthy candidates for drugs against GBM. The detailed analysis carried out in this study provides a substantial basis for the prospective design and development of novel 4-phenylquinazoline-2-carboxamide compounds as TSPO ligands capable of inducing apoptosis in cancer cells.