CoMFA, CoMSIA, Topomer CoMFA, HQSAR, molecular docking and molecular dynamics simulations study of triazine morpholino derivatives as mTOR inhibitors for the treatment of breast cancer

mTOR has become a promising target for many types of cancer like breast, lung and renal cell carcinoma. CoMFA, CoMSIA, Topomer CoMFA and HQSAR were performed on the series of 39 triazine morpholino derivatives. CoMFA analysis showed q2 value of 0.735, r2cv value of 0.722 and r2pred value of 0.769. CoMSIA analysis (SEHD) showed q2 value of 0.761, r2cv value of 0.775 and r2pred value of 0.651. Topomer CoMFA analysis showed q2 value of 0.693, r2 (conventional correlation coefficient) value of 0.940 and r2pred value of 0.720. HQSAR analysis showed q2,r2and r2pred values of 0.694, 0.920 and 0.750, respectively. HQSAR analysis with the combination of atomic number (A), bond type (B) and atomic connections showed q2 and r2 values of 0.655 and 0.891, respectively. Contour maps from all studies provided significant insights. Molecular docking studies with molecular dynamics simulations were carried out on the highly potent compound 36. Furthermore, four acridine derivatives were designed and docking results of these designed compounds showed the same interactions as that of the standard PI-103 which proved the efficiency of 3D-QSAR and MD/MS study. In future, this study might be useful prior to synthesis for the designing of novel mTOR inhibitors.

[1]  N. Pavletich,et al.  mTOR kinase structure, mechanism and regulation by the rapamycin-binding domain , 2013, Nature.

[2]  H. Bhatt,et al.  3D-QSAR, molecular dynamics simulations, and molecular docking studies on pyridoaminotropanes and tetrahydroquinazoline as mTOR inhibitors , 2017, Molecular Diversity.

[3]  David M Sabatini,et al.  mTOR and cancer: many loops in one pathway. , 2009, Current opinion in cell biology.

[4]  C. García-echeverría.  Allosteric and ATP-competitive kinase inhibitors of mTOR for cancer treatment. , 2010, Bioorganic & medicinal chemistry letters.

[5]  Eva Maria Ciruelos Gil,et al.  Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer , 2014 .

[6]  Judy Lucas,et al.  Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. , 2010, Journal of medicinal chemistry.

[7]  J. Gasteiger,et al.  ITERATIVE PARTIAL EQUALIZATION OF ORBITAL ELECTRONEGATIVITY – A RAPID ACCESS TO ATOMIC CHARGES , 1980 .

[8]  T. Ran,et al.  3D-QSAR and molecular fragment replacement study on diaminopyrimidine and pyrrolotriazine ALK inhibitors , 2014 .

[9]  Rui Wang,et al.  3D-QSAR and docking studies of 3-Pyridine heterocyclic derivatives as potent PI3K/mTOR inhibitors , 2013 .

[10]  Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[11]  T. Ran,et al.  A selectivity study on mTOR/PI3Kα inhibitors by homology modeling and 3D-QSAR , 2011, Journal of Molecular Modeling.

[12]  L. Feldberg,et al.  PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor. , 2010, Bioorganic & medicinal chemistry letters.

[13]  A. Dixit,et al.  Development of CoMFA, advance CoMFA and CoMSIA models in pyrroloquinazolines as thrombin receptor antagonist. , 2004, Bioorganic & medicinal chemistry.

[14]  Hua Gao,et al.  3D-QSAR modeling and molecular docking study on Mer kinase inhibitors of pyridine-substituted pyrimidines , 2014, Molecular Diversity.

[15]  M. Filipits,et al.  mTOR inhibitors in breast cancer: a systematic review. , 2012, Gynecologic oncology.

[16]  Jiri Polivka,et al.  Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. , 2014, Pharmacology & therapeutics.

[17]  David M Sabatini,et al.  An expanding role for mTOR in cancer. , 2005, Trends in molecular medicine.

[18]  B. Kumar,et al.  Structural investigations of anthranilimide derivatives by CoMFA and CoMSIA 3D-QSAR studies reveal novel insight into their structures toward glycogen phosphorylase inhibition , 2011, SAR and QSAR in environmental research.

[19]  Anshuman Dixit,et al.  An investigation of structurally diverse carbamates for acetylcholinesterase (AChE) inhibition using 3D-QSAR analysis. , 2008, Journal of molecular graphics & modelling.

[20]  X. Zheng,et al.  Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. , 2011, Drug discovery today.

[21]  V. Vyas,et al.  CoMFA and CoMSIA studies on C-aryl glucoside SGLT2 inhibitors as potential anti-diabetic agents , 2013, SAR and QSAR in environmental research.

[22]  B. Leyland-Jones,et al.  Promise of rapalogues versus mTOR kinase inhibitors in subset specific breast cancer: old targets new hope. , 2013, Cancer treatment reviews.

[23]  G. N. Sastry,et al.  CoMFA, CoMSIA, kNN MFA and docking studies of 1,2,4-oxadiazole derivatives as potent caspase-3 activators , 2017 .

[24]  Julio Caballero,et al.  3D-QSAR (CoMFA and CoMSIA) and pharmacophore (GALAHAD) studies on the differential inhibition of aldose reductase by flavonoid compounds. , 2010, Journal of molecular graphics & modelling.

[25]  C. G. Gadhe,et al.  In Silico Quantitative Structure-Activity Relationship Studies on P-gp Modulators of Tetrahydroisoquinoline-Ethyl-Phenylamine Series , 2011, BMC Structural Biology.

[26]  R. Cramer,et al.  Topomer CoMFA: a design methodology for rapid lead optimization. , 2003, Journal of medicinal chemistry.

[27]  H. Husseinzadeh,et al.  mTOR inhibitors and their clinical application in cervical, endometrial and ovarian cancers: a critical review. , 2014, Gynecologic oncology.

[28]  Imran Ali,et al.  Cancer Scenario in India with Future Perspectives , 2011 .

[29]  Gyanendra Pandey,et al.  3D QSAR Studies on Protein Tyrosine Phosphatase 1B Inhibitors: Comparison of the Quality and Predictivity among 3D QSAR Models Obtained from Different Conformer-Based Alignments , 2006, J. Chem. Inf. Model..

[30]  J. Sridhar,et al.  QSAR models of cytochrome P450 enzyme 1A2 inhibitors using CoMFA, CoMSIA and HQSAR , 2011, SAR and QSAR in environmental research.

[31]  Ruisheng Zhang,et al.  CoMFA and CoMSIA 3D-QSAR studies on quionolone caroxylic acid derivatives inhibitors of HIV-1 integrase. , 2010, European journal of medicinal chemistry.

[32]  Adeayo O. Ajala,et al.  3D-QSAR Topomer CoMFA Studies on 10 N-Substituted Acridone Derivatives , 2012 .

[33]  Shi-Yong Sun,et al.  mTOR kinase inhibitors as potential cancer therapeutic drugs. , 2013, Cancer letters.

[34]  G. UgarkarApoorva,et al.  Extracting structural requirements for activity of GPR119 agonists: a hologram quantitative structure activity relationship (HQSAR) study , 2014 .