STRUCTURE-BASED MULTITARGETED MOLECULAR DOCKING ANALYSIS OF PYRAZOLE-CONDENSED HETEROCYCLICS AGAINST LUNG CANCER

Authors

  • JAINEY P. JAMES Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Pharmaceutical Chemistry, Deralakatte, Mangaluru 575018, Karnataka, India
  • AISWARYA T. C. Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Pharmaceutical Chemistry, Deralakatte, Mangaluru 575018, Karnataka, India
  • SNEH PRIYA Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Pharmaceutical Chemistry, Deralakatte, Mangaluru 575018, Karnataka, India
  • DIVYA JYOTHI Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Pharmaceutical Chemistry, Deralakatte, Mangaluru 575018, Karnataka, India
  • SHESHAGIRI R. DIXIT Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India

DOI:

https://doi.org/10.22159/ijap.2021v13i6.42801

Keywords:

Lung cancer, Pyrazolopyrimidines, Pyrazolopyridines, Molecular docking, Pharmacophore modeling, Anticancer activities

Abstract

Objective: The significant drawbacks of chemotherapy are that it destroys healthy cells, resulting in adverse effects. Hence, there is a need to adopt new techniques to develop cancer-specific chemicals that target the molecular pathways in a non-toxic fashion. This study aims to screen pyrazole-condensed heterocyclics for their anticancer activities and analyse their enzyme inhibitory potentials EGFR, ALK, VEGFR and TNKS receptors.

Methods: The structures of the compounds were confirmed by IR, NMR and Mass spectral studies. The in silico techniques applied in this study were molecular docking and pharmacophore modeling to analyse the protein-ligand interactions, as they have a significant role in drug discovery. Drug-likeness properties were assessed by the Lipinski rule of five and ADMET properties. Anticancer activity was performed by in vitro MTT assay on lung cancer cell lines.

Results: The results confirm that all the synthesised pyrazole derivatives interacted well with the selected targets showing docking scores above-5 kcal/mol. Pyrazole 2e interacted well with all the four lung cancer targets with its stable binding mode and was found to be potent as per the in vitro reports, followed by compounds 3d and 2d. Pharmacophore modeling exposed the responsible features responsible for the anticancer action. ADMET properties reported that all the compounds were found to have properties within the standard limit. The activity spectra of the pyrazoles predicted that pyrazolopyridines (2a-2e) are more effective against specific receptors such as EGFR, ALK and Tankyrase.

Conclusion: Thus, this study suggests that the synthesised pyrazole derivatives can be further investigated to validate their enzyme inhibitory potentials by in vivo studies.

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References

Prabhu VV, Devaraj N. Epidermal growth factor receptor tyrosine kinase: A potential target in the treatment of non-small-cell lung carcinoma. J Environ Pathol Toxicol Oncol. 2017;36(2):151-8. doi: 10.1615/JEnvironPatholToxicolOncol. 2017018341, PMID 2017018341.

Alferez D, Wilkinson RW, Watkins J, Poulsom R, Mandir N, Wedge SR, Pyrah IT, Smith NR, Jackson L, Ryan AJ, Goodlad RA. Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in Apc(Min/+) mice. Mol Cancer Ther. 2008;7(3):590-8. doi: 10.1158/1535-7163.MCT-07-0433, PMID 18347145.

Antonicelli A, Cafarotti S, Indini A, Galli A, Russo A, Cesario A, Lococo FM, Russo P, Mainini AF, Bonifati LG, Nosotti M, Santambrogio L, Margaritora S, Granone PM, Dutly AE. EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci. 2013;10(3):320-30. doi: 10.7150/ijms.4609, PMID 23423768.

Castanon E, Martin P, Rolfo C, Fusco JP, Ceniceros L, Legaspi J, Santisteban M, Gil-Bazo I. Epidermal growth factor receptor targeting in non-small cell lung cancer: revisiting different strategies against the same target. Curr Drug Targets. 2014;15(14):1273-83.doi: 10.2174/138945011514141216092935, PMID 25511613.

Jänne PA, Yang JCH, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non–small-cell lung cancer. N Engl J Med. 2015;372(18):1689-99. doi: 10.1056/NEJMoa1411817, PMID 25923549.

Gerber DE, Minna JD. ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. Cancer Cell. 2010;18(6):548-51. doi: 10.1016/j.ccr.2010.11.033, PMID 21156280.

Sang J, Acquaviva J, Friedland JC, Smith DL, Sequeira M, Zhang C, Jiang Q, Xue L, Lovly CM, Jimenez JP, Shaw AT, Doebele RC, He S, Bates RC, Camidge DR, Morris SW, El-Hariry I, Proia DA. Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non–small cell lung cancer. Cancer Discovery. 2013;3(4):430-43. doi: 10.1158/2159-8290.CD-12-0440, PMID 23533265.

Nguyen-Ngoc T, Bouchaab H, Adjei AA, Peters S. BRAF alterations as therapeutic targets in non–small-cell lung cancer. J Thorac Oncol. 2015;10(10):1396-403. doi: 10.1097/JTO.0000000000000644, PMID 26301799.

Gautschi O, Milia J, Cabarrou B, Bluthgen MV, Besse B, Smit EF, Wolf J, Peters S, Früh M, Koeberle D, Oulkhouir Y, Schuler M, Curioni-Fontecedro A, Huret B, Kerjouan M, Michels S, Pall G, Rothschild S, Schmid-Bindert G, Scheffler M, Veillon R, Wannesson L, Diebold J, Zalcman G, Filleron T, Mazières J. Targeted therapy for patients with BRAF-mutant lung cancer: results from the European EURAF cohort. J Thorac Oncol. 2015;10(10):1451-7. doi: 10.1097/JTO.0000000000000625, PMID 26200454.

Feng Y, Hu J, Ma J, Feng K, Zhang X, Yang S, Wang W, Zhang J, Zhang Y. RNAi-mediated silencing of VEGF-C inhibits non-small cell lung cancer progression by simultaneously down-regulating the CXCR4, CCR7, VEGFR-2 and VEGFR-3-dependent axes-induced ERK, p38 and AKT signalling pathways. Eur J Cancer. 2011;47(15):2353-63. doi: 10.1016/j.ejca.2011.05.006, PMID 21680174.

Villaruz LC, Socinski MA. The role of anti-angiogenesis in non-small-cell lung cancer: an update. Curr Oncol Rep. 2015;17(6):26. doi: 10.1007/s11912-015-0448-y, PMID 25947099.

Yang J, Chen J, He J, Li J, Shi J, Cho WC, Liu X. Wnt signaling as potential therapeutic target in lung cancer. Expert Opin Ther Targets. 2016;20(8):999-1015. doi: 10.1517/14728222. 2016.1154945, PMID 26882052.

Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol. 2018;12(1):3-20. doi: 10.1002/1878-0261.12155, PMID 29124875.

Shackelford RE, Vora M, Mayhall K, Cotelingam J. ALK-rearrangements and testing methods in non-small cell lung cancer: a review. Genes Cancer. 2014;5(1-2):1-14. doi: 10.18632/genes and cancer.3, PMID 24955213.

Alevizakos M, Kaltsas S, Syrigos KN. The VEGF pathway in lung cancer. Cancer Chemother Pharmacol. 2013;72(6):1169-81. doi: 10.1007/s00280-013-2298-3, PMID 24085262.

Riffell JL, Lord CJ, Ashworth A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat Rev Drug Discovery. 2012;11(12):923-36. doi: 10.1038/nrd3868, PMID 23197039.

Santarpia M, Liguori A, Karachaliou N, Gonzalez-Cao M, Daffina MG, D’Aveni A, Marabello G, Altavilla G, Rosell R. Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy. Lung Cancer (Auckl). 2017;8:109-25. doi: 10.2147/LCTT.S119644, PMID 28860885.

Descourt R, Perol M, Rousseau-Bussac G, Planchard D, Mennecier B, Wislez M, Cortot A, Guisier F, Galland L, Dô P, Schott R, Dansin E, Arrondeau J, Auliac JB, Chouaid C. Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study). Lung Cancer. 2019;136:109-14. doi: 10.1016/j.lungcan.2019.08.010, PMID 31491676.

Martinelli E, Troiani T, Morgillo F, Rodolico G, Vitagliano D, Morelli MP, Tuccillo C, Vecchione L, Capasso A, Orditura M, De Vita F, Eckhardt SG, Santoro M, Berrino L, Ciardiello F. Synergistic antitumor activity of sorafenib in combination with epidermal growth factor receptor inhibitors in colorectal and lung cancer cells. Clin Cancer Res. 2010;16(20):4990-5001. doi: 10.1158/1078-0432.CCR-10-0923, PMID 20810384.

Shukla P, Sharma A, Fageria L, Chowdhury R. Novel spiro/non-spiro pyranopyrazoles: eco-friendly synthesis, in vitro anticancer activity, DNA binding, and in-silico docking studies. Curr Bioact Compd. 2019;15(2):257-67. doi: 10.2174/1573407213666170828165512.

Pj J, K IB. Synthesis, in silico physicochemical properties and biological activities of some pyrazoline derivatives. Asian J Pharm Clin Res. 2017;10(4):456-9. doi: 10.22159/ ajpcr.2017.v10i4.17093.

Bhat IS, Jainey PJ. Antimicrobial studies of some substituted pyrazoline derivatives derived from acetyl hydrazines. Asian J Pharm Clin Res. 2014;7(4):237-9.

James JP, Kumar P, Kumar A, Bhat KI, Shastry CS. In silico anticancer evaluation, molecular docking and pharmacophore modeling of flavonoids against various cancer targets. Lett Drug Des Discovery. 2020 Dec 1;17(12):1485-501. doi: 10.2174/1570180817999200730164222.

Kodical DD, James JP, Deepthi K, Kumar P, Cyriac C, Gopika KV. ADMET, Molecular docking studies and binding energy calculations of pyrimidine-2-thiol derivatives as cox inhibitors. Res J Pharm Technol. 2020 Sep 1;13(9):4200-6. doi: 10.5958/0974-360X.2020.00742.8.

Salaheldin AM, Oliveira Campos AMF, Rodrigues LM. Heterocyclic synthesis with nitriles: synthesis of pyrazolopyrimidine and pyrazolopyridine derivatives. Synth Commun. 2009;39(7):1186-95. doi: 10.1080/00397910802517814.

Schrödinger. Schrödinger Release; 2019. Vol. 4. Available from: https://www.schrodinger.com. [Last accessed on 10 Jul 2021]

PDB database. Available from: https://www.rcsb.org/ structure/4WKQ. [Last accessed on 10 Jul 2021].

Michellys PY, Chen B, Jiang T, Jin Y, Lu W, Marsilje TH, Pei W, Uno T, Zhu X, Wu B, Nguyen TN, Bursulaya B, Lee C, Li N, Kim S, Tuntland T, Liu B, Sun F, Steffy A, Hood T. Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors. Bioorg Med Chem Lett. 2016;26(3):1090-6. doi: 10.1016/j.bmcl.2015.11.049, PMID 26750252.

McTigue M, Murray BW, Chen JH, Deng YL, Solowiej J, Kania RS. Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc Natl Acad Sci USA 2012;109(45):18281-9. doi: 10.1073/pnas.1207759109, PMID 22988103.

Johannes JW, Almeida L, Barlaam B, Boriack Sjodin PA, Casella RP, Croft RA, Dishington AP, Gingipalli L, Gu C, Hawkins JL, Holmes JL, Howard T, Huang J, Ioannidis S, Kazmirski S, Lamb ML, McGuire TM, Moore JE, Ogg D, Patel A, Pike KG, Pontz T, Robb GR, Su N, Wang H, Wu X, Zhang HJ, Zhang Y, Zheng X, Wang T. Pyrimidinone nicotinamide mimetics as selective tankyrase and wnt pathway inhibitors suitable for in vivo pharmacology. ACS Med Chem Lett. 2015;6(3):254-9. doi: 10.1021/ml5003663, PMID 25815142.

Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006;49(21):6177-96. doi: 10.1021/jm051256o, PMID 17034125.

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev. 2001;46(1-3):3-26. doi: 10.1016/s0169-409x(00)00129-0, PMID 11259830.

Druzhilovskiy DS, Rudik AV, Filimonov DA, Lagunin AA, Gloriozova TA, Poroikov VV. Online resources for the prediction of biological activity of organic compounds. Russ Chem Bull. 2016;65(2):384-93. doi: 10.1007/s11172-016-1310-6.

Denizot F, Lang R. Rapid colorimetric assay for cell growth and survival. J Immunol Method. 1986;89(2):271-7. doi: 10.1016/0022-1759(86)90368-6.

El-Kalyoubi SA. Synthesis and anticancer evaluation of some novel pyrimido[5,4-e][1,2,4]triazines and pyrazolo[3,4-d]pyrimidine using DMF-DMA as methylating and cyclizing agent. Chem Cent J. 2018;12(1):64. doi: 10.1186/s13065-018-0424-3, PMID 29796716.

Ismail NSM, Ali EMH, Ibrahim DA, Serya RAT, Abou El Ella DA. Pyrazolo [3, 4-d] pyrimidine-based scaffold derivatives targeting kinases as anticancer agents. Future J Pharm Sci. 2016;2(1):20-30. doi: 10.1016/j.fjps.2016.02.002.

Sun N, Ji H, Wang W, Zhu Q, Cao M, Zang Q. Inhibitory effect of dexamethasone on residual Lewis lung cancer cells in mice following palliative surgery. Oncol Lett. 2017;13(1):356-62. doi: 10.3892/ol.2016.5422, PMID 28123567.

Chedid M, Eissa HO, Engler TA, Furness KW, Woods TA, Wrobleski AD. US Patent No. 9,624,218. Washington, DC: US Patent and Trademark Office; 2017.

Zhang J, Song Y, Liang Y, Zou H, Zuo P, Yan M, Jing S, Li T, Wang Y, Li D, Zhang T, Wei Z. Cucurbitacin IIa interferes with EGFR-MAPK signaling pathway leads to proliferation inhibition in A549 cells. Food Chem Toxicol. 2019 Oct 1;132:110654. doi: 10.1016/j.fct.2019.110654.

Vinod Prabhu V, Elangovan P, Niranjali Devaraj S, Sakthivel KM. Targeting apoptosis by 1, 2-diazole through regulation of EGFR, Bcl-2 and CDK-2 mediated signaling pathway in human non-small cell lung carcinoma A549 cells. Gene. 2018 Dec 30;679:352-9. doi: 10.1016/j.gene.2018.09.014, PMID 30218747.

Shi L, Zhang S, Wu H, Zhang L, Dai X, Hu J, Xue J, Liu T, Liang Y, Wu G. MiR-200c increases the radiosensitivity of non-small-cell lung cancer cell line A549 by targeting the VEGF-VEGFR2 pathway. PLOS ONE. 2013 Oct 30;8(10):e78344. doi: 10.1371/journal.pone.0078344, PMID 24205206.

Yang L, Li G, Zhao L, Pan F, Qiang J, Han S. Blocking the PI3K pathway enhances the efficacy of ALK-targeted therapy in EML4-ALK-positive non-small-cell lung cancer. Tumour Biol. 2014 Oct;35(10):9759-67. doi: 10.1007/s13277-014-2252-y, PMID 24972969.

Li C, Zheng X, Han Y, Lv Y, Lan F, Zhao J. XAV939 inhibits the proliferation and migration of lung adenocarcinoma A549 cells through the WNT pathway. Oncol Lett. 2018 Jun 1;15(6):8973-82. doi: 10.3892/ol.2018.8491, PMID 29805633.

Li P, Zhao S, Hu Y. SFRP2 modulates non-small cell lung cancer A549 cell apoptosis and metastasis by regulating mitochondrial fission via Wnt pathways. Mol Med Rep. 2019 Aug 1;20(2):1925-32. doi: 10.3892/mmr.2019.10393, PMID 31257495.

Published

07-11-2021

How to Cite

JAMES, J. P., T. C., A., PRIYA, S., JYOTHI, D., & R. DIXIT, S. (2021). STRUCTURE-BASED MULTITARGETED MOLECULAR DOCKING ANALYSIS OF PYRAZOLE-CONDENSED HETEROCYCLICS AGAINST LUNG CANCER. International Journal of Applied Pharmaceutics, 13(6), 157–169. https://doi.org/10.22159/ijap.2021v13i6.42801

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