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

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 (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. 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.

[1]  D. Nutt,et al.  Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. , 2006, Trends in pharmacological sciences.

[2]  Sukriti Goyal,et al.  Mechanistic insights into mode of actions of novel oligopeptidase B inhibitors for combating leishmaniasis , 2014, Journal of Molecular Modeling.

[3]  Jesús S. Dehesa,et al.  Insight into the informational-structure behavior of the Diels-Alder reaction of cyclopentadiene and maleic anhydride , 2014, Journal of Molecular Modeling.

[4]  Barbara Costa,et al.  Structure-activity relationship refinement and further assessment of 4-phenylquinazoline-2-carboxamide translocator protein ligands as antiproliferative agents in human glioblastoma tumors. , 2014, Journal of medicinal chemistry.

[5]  Peter Canoll,et al.  Magnetic Resonance Imaging Characteristics of Glioblastoma Multiforme: Implications for Understanding Glioma Ontogeny , 2010, Neurosurgery.

[6]  Sukriti Goyal,et al.  Development of Dual Inhibitors against Alzheimer's Disease Using Fragment-Based QSAR and Molecular Docking , 2014, BioMed research international.

[7]  M. Gavish,et al.  The role of 18 kDa mitochondrial translocator protein (TSPO) in programmed cell death, and effects of steroids on TSPO expression. , 2012, Current molecular medicine.

[8]  J. Dhanjal,et al.  Molecular modelling studies on flavonoid derivatives as dual site inhibitors of human acetyl cholinesterase using 3D-QSAR, pharmacophore and high throughput screening approaches , 2014, Medicinal Chemistry Research.

[9]  Sukriti Goyal,et al.  Computational design of novel flavonoid analogues as potential AChE inhibitors: analysis using group-based QSAR, molecular docking and molecular dynamics simulations , 2015, Structural Chemistry.

[10]  Gerrit Groenhof,et al.  GROMACS: Fast, flexible, and free , 2005, J. Comput. Chem..

[11]  P. Choudhari,et al.  Application of group-based QSAR on 2-thioxo-4-thiazolidinone for development of potent anti-diabetic compounds , 2017 .

[12]  Carl Caleman,et al.  GROMACS molecule & liquid database , 2012, Bioinform..

[13]  Christopher G Willett,et al.  Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  Sukriti Goyal,et al.  Computational identification of novel natural inhibitors of glucagon receptor for checking type II diabetes mellitus , 2014, BMC Bioinformatics.

[15]  Sukriti Goyal,et al.  Group-based QSAR and molecular dynamics mechanistic analysis revealing the mode of action of novel piperidinone derived protein-protein inhibitors of p53-MDM2. , 2014, Journal of molecular graphics & modelling.

[16]  Ricardo J Komotar,et al.  Genomics of human glioblastoma multiforme: a glimpse of the future. , 2008, Neurosurgery.

[17]  M. Gavish,et al.  Role of mitochondrial translocator protein (18 kDa) on mitochondrial- related cell death processes. , 2013, Recent patents on endocrine, metabolic & immune drug discovery.

[18]  Peter Canoll,et al.  THE SURVIVAL IMPACT OF POSTOPERATIVE INFECTION IN PATIENTS WITH GLIOBLASTOMA MULTIFORME , 2009, Neurosurgery.

[19]  J. Dhanjal,et al.  Fragment based group QSAR and molecular dynamics mechanistic studies on arylthioindole derivatives targeting the α-β interfacial site of human tubulin , 2014, BMC Genomics.

[20]  Michael Kassiou,et al.  The Translocator Protein , 2011, The Journal of Nuclear Medicine.

[21]  Sukriti Goyal,et al.  Novel Fragment‐Based QSAR Modeling and Combinatorial Design of Pyrazole‐Derived CRK3 Inhibitors as Potent Antileishmanials , 2014, Chemical biology & drug design.

[22]  Peter M. Kasson,et al.  Gromacs User Manual Version 4.6 , 2013 .