GQSAR modeling and combinatorial library generation of 4-phenylquinazoline-2-carboxamide derivatives as antiproliferative agents in human Glioblastoma tumors. (August 2017)

• Record Type: Journal Article
• Authors: Goswami, Debolina; Goyal, Sukriti; Jamal, Salma; Jain, Ritu; Wahi, Divya; Grover, Abhinav
• Is Part Of: Computational biology and chemistry. Volume 69(2017)
• Page Start: 147
• Page End: 152
• Publication Date: 2017-08
• Subjects: GBM Glioblastoma multiforme -- TSPO translocator protein -- MPTP mitochondrial permeability transition pore -- ANT adenine nucleotide transporter -- VDAC voltage dependent anion channel -- QSAR quantitative structure activity relationship -- GQSAR Group QSAR -- ETA Extended Topological Atom -- LOO leave-one-out -- EQC N-ethyl-4-[2-methyl-4-(2-methylpropyl)phenyl]quinazoline-2-carboxamide -- BQC N-butyl-4-(4-ethyl-2-methylphenyl)quinazoline-2-carboxamide; TSPO -- QSAR -- Glioblastoma multiforme -- Combinatorial library -- Docking -- Inhibitor -- Drug; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2017.03.017
• Languages: English
• ISSNs: 1476-9271

Abstract

Abstract: Background: TSPO 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. Results: Model developed showed satisfactory statistical parameters for the experimentally reported dataset (r 2 = 0.8259, q 2 = 0.6788, pred_r 2 = 0.8237 and F-test = 37.9). Low standard error values (r 2 _se = 0.253, q 2 _se = 0.34, pred_r 2 _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. Conclusion: The 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.