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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

Computational Studies of bis-2-Oxoindoline Succinohydrazides and their In Vitro Cytotoxicity

Author(s): Ravi Jarapula, Vishnu N. Badavath, Shriram Rekulapally and Sarangapani Manda*

Volume 16, Issue 3, 2020

Page: [270 - 280] Pages: 11

DOI: 10.2174/1573409915666190117122139

Price: $65

Abstract

Background: The discovery of clinically relevant EGFR inhibitors for cancer therapy has proven to be a challenging task. To identify novel and potent EGFR inhibitors, the quantitative structure-activity relationship (QSAR) and molecular docking approach became a very useful and largely widespread technique for drug design.

Methods: We performed the in vitro cytotoxic activity on HEPG-2 cell line and earlier on MCF-7 and A 549 by using MTT assay method. The development of 3D QSAR model of N1,N4-bis(2-oxoindolin-3- ylidene) succinohydrazides using the stepwise-backward variable methods to generate Multiple Linear Regression method elucidates the structural properties required for EGFR inhibitory activity and also perform the Molecular Docking studies on EGFR (PDB ID:1M17). Further, we analysed for Lipinski’s rule of five to evaluate the drug-likeness and established in silico ADMET properties.

Results: The resulting cytotoxicity (IC50) values ranged from 9.34 to 100 μM and compared with cisplatin as a standard. Among the series of compounds, 6j showed good cytotoxic activity on HEPG-2 cell line with 9.34 μM, IC50 value. Most of the evaluated compounds showed good antitumor activity on HEPG-2 than MCF-7and A549. The developed 3D QSAR Multiple Linear Regression models are statistically significant with non-cross-validated correlation coefficient r2 = 0.9977, cross-validated correlation coefficient q2 = 0.902 and predicted_r2 = 0.9205. Molecular docking studies on EGFR (PDB ID: 1M17) results, compounds 6d, 6j and 6l showed good dock/PLP scores i.e. -81.28, -73.98 and -75.37, respectively, by interacting with Leu-694, Val-702 and Gly-772 amino acids via hydrophobic and hydrogen bonds with Asn818 and Met- 769. Further, we analysed drug-likeness and established in silico ADMET properties.

Conclusion: The results of 3D QSAR studies suggest that the electrostatic and steric descriptors influence the cytotoxic activity of succinohydrazides. From the molecular docking studies, it is evident that hydrophobic, hydrogen and Van Der Waal’s interactions determine binding affinities. In addition to this, druglikeness and ADMET properties were analysed. It is evident that there is a correlation between the QSAR and docking results. Compound 6j was found to be too lipophilic due to its dihalo substitution on isatin nucleus, and can act as a lead molecule for further and useful future development of new EGFR Inhibitors.

Keywords: Bis-2-Oxoindoline succinohydrazide derivatives, cytotoxicity, 3D QSAR-MLR, EGFR, ADMET, molecular docking studies.

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[1]
Shobeiri, N.; Rashedi, M.; Mosaffa, F.; Zarghi, A.; Ghandadi, M.; Ghasemi, A.; Ghodsi, R. Synthesis and biological evaluation of quinoline analogues of flavones as potential anticancer agents and tubulin polymerization inhibitors. Eur. J. Med. Chem., 2016, 114, 14-23.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.069] [PMID: 26974371]
[2]
Anand, P.; Kunnumakkara, A.B.; Sundaram, C.; Harikumar, K.B.; Tharakan, S.T.; Lai, O.S.; Sung, B.; Aggarwal, B.B. Cancer is a preventable disease that requires major lifestyle changes. Pharm. Res., 2008, 25(9), 2097-2116.
[http://dx.doi.org/10.1007/s11095-008-9661-9] [PMID: 18626751]
[3]
Cheng, Y.; Cui, W.; Chen, Q.; Tung, C-H.; Ji, M.; Zhang, F. The molecular mechanism studies of chirality effect of PHA-739358 on Aurora kinase A by molecular dynamics simulation and free energy calculations. J. Comput. Aided Mol. Des., 2011, 25(2), 171-180.
[http://dx.doi.org/10.1007/s10822-010-9408-7] [PMID: 21222017]
[4]
Wu, K-W.; Chen, P-C.; Wang, J.; Sun, Y-C. Computation of relative binding free energy for an inhibitor and its analogs binding with Erk kinase using thermodynamic integration MD simulation. J. Comput. Aided Mol. Des., 2012, 26(10), 1159-1169.
[http://dx.doi.org/10.1007/s10822-012-9606-6] [PMID: 22986633]
[5]
Levitzki, A. Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical performance. Annu. Rev. Pharmacol. Toxicol., 2013, 53, 161-185.
[http://dx.doi.org/10.1146/annurev-pharmtox-011112-140341] [PMID: 23043437]
[6]
Cohen, P. Protein kinases--the major drug targets of the twenty-first century? Nat. Rev. Drug Discov., 2002, 1(4), 309-315.
[http://dx.doi.org/10.1038/nrd773] [PMID: 12120282]
[7]
Malumbres, M.; Barbacid, M. Cell cycle kinases in cancer. Curr. Opin. Genet. Dev., 2007, 17(1), 60-65.
[http://dx.doi.org/10.1016/j.gde.2006.12.008] [PMID: 17208431]
[8]
Roymans, D.; Slegers, H. Phosphatidylinositol 3-kinases in tumor progression. Eur. J. Biochem., 2001, 268(3), 487-498.
[http://dx.doi.org/10.1046/j.1432-1327.2001.01936.x] [PMID: 11168386]
[9]
Lv, P-C.; Zhou, C-F.; Chen, J.; Liu, P-G.; Wang, K-R.; Mao, W-J.; Li, H-Q.; Yang, Y.; Xiong, J.; Zhu, H-L. Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors. Bioorg. Med. Chem., 2010, 18(1), 314-319.
[http://dx.doi.org/10.1016/j.bmc.2009.10.051] [PMID: 19914835]
[10]
Ullrich, A.; Schlessinger, J. Signal transduction by receptors with tyrosine kinase activity. Cell, 1990, 61(2), 203-212.
[http://dx.doi.org/10.1016/0092-8674(90)90801-K] [PMID: 2158859]
[11]
Bridges, A.J. Chemical inhibitors of protein kinases. Chem. Rev., 2001, 101(8), 2541-2572.
[http://dx.doi.org/10.1021/cr000250y] [PMID: 11749388]
[12]
Grünwald, V.; Hidalgo, M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J. Natl. Cancer Inst., 2003, 95(12), 851-867.
[http://dx.doi.org/10.1093/jnci/95.12.851] [PMID: 12813169]
[13]
Tamura, K.; Fukuoka, M. Gefitinib in non-small cell lung cancer. Expert Opin. Pharmacother., 2005, 6(6), 985-993.
[http://dx.doi.org/10.1517/14656566.6.6.985] [PMID: 15952926]
[14]
Reck, M.; van Zandwijk, N.; Gridelli, C.; Baliko, Z.; Rischin, D.; Allan, S.; Krzakowski, M.; Heigener, D. Erlotinib in advanced non-small cell lung cancer: efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment study. J. Thorac. Oncol., 2010, 5(10), 1616-1622.
[http://dx.doi.org/10.1097/JTO.0b013e3181f1c7b0] [PMID: 20736854]
[15]
Smith, J. Erlotinib: small-molecule targeted therapy in the treatment of non-small-cell lung cancer. Clin. Ther., 2005, 27(10), 1513-1534.
[http://dx.doi.org/10.1016/j.clinthera.2005.10.014] [PMID: 16330289]
[16]
Reddy, S.S.; Pallela, R.; Kim, D-M.; Won, M-S.; Shim, Y-B. Synthesis and evaluation of the cytotoxic activities of some isatin derivatives. Chem. Pharm. Bull. (Tokyo), 2013, 61(11), 1105-1113.
[http://dx.doi.org/10.1248/cpb.c13-00400] [PMID: 24005772]
[17]
Jarapula, R.; Rekulapally, S.; Cidda, M. arangapani M. Synthesis, in Vitro Anticancer and Molecular Docking Studies of New Bisisatins as Anticancer Agents. World J. Pharm. Pharm. Sci., 2017, 6(9), 1037-1053.
[18]
Vishnu Nayak, B.; Ciftci-Yabanoglu, S.; Jadav, S.S.; Jagrat, M.; Sinha, B.N.; Ucar, G.; Jayaprakash, V. Monoamine oxidase inhibitory activity of 3,5-biaryl-4,5-dihydro-1H-pyrazole-1-carboxylate derivatives. Eur. J. Med. Chem., 2013, 69, 762-767.
[http://dx.doi.org/10.1016/j.ejmech.2013.09.010] [PMID: 24099995]
[19]
Badavath, V.N.; Ucar, G.; Sinha, B.N.; Mondal, S.K.; Jayaprakash, V. Monoamine Oxidase Inhibitory Activity of Novel Pyrazoline Analogues: Curcumin Based Design and Synthesis‐II. ChemistrySelect, 2016, 1(18), 5879-5884.
[http://dx.doi.org/10.1002/slct.201600914]
[20]
Badavath, V.N.; Baysal, İ.; Ucar, G.; Sinha, B.N.; Jayaprakash, V. Monoamine Oxidase Inhibitory Activity of Novel Pyrazoline Analogues: Curcumin Based Design and Synthesis. ACS Med. Chem. Lett., 2015, 7(1), 56-61.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00326] [PMID: 26819666]
[21]
Nath, C.; Badavath, V.N.; Thakur, A.; Ucar, G.; Acevedo, O.; Mohd Siddique, M.U.; Jayaprakash, V. Curcumin-based pyrazoline analogues as selective inhibitors of human monoamine oxidase A. MedChemComm, 2018, 9(7), 1164-1171.
[http://dx.doi.org/10.1039/C8MD00196K] [PMID: 30109004]
[22]
Jain, S.V.; Ghate, M.; Bhadoriya, K.S.; Bari, S.B.; Chaudhari, A.; Borse, J.S.II 2D, 3D-QSAR and docking studies of 1,2,3-thiadiazole thioacetanilides analogues as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Org. Med. Chem. Lett., 2012, 2(1), 22.
[http://dx.doi.org/10.1186/2191-2858-2-22] [PMID: 22691718]
[23]
Yasuda, H.; Park, E.; Yun, C-H.; Sng, N.J.; Lucena-Araujo, A.R.; Yeo, W-L.; Huberman, M.S.; Cohen, D.W.; Nakayama, S.; Ishioka, K. Structural,Biochemical, and Clinical Characterization of Epidermal Growth Factor Rreceptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer. Sci. Transl. Med., 2013.
[24]
Gehlhaar, D.K.; Verkhivker, G.M.; Rejto, P.A.; Sherman, C.J.; Fogel, D.B.; Fogel, L.J.; Freer, S.T. Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. Chem. Biol., 1995, 2(5), 317-324.
[http://dx.doi.org/10.1016/1074-5521(95)90050-0] [PMID: 9383433]
[25]
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. AdmetSAR: A Comprehensive Source and Free Tool for Assessment of Chemical ADMET Properties; ACS Publications, 2012.

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