STRUCTURE-BASED MULTITARGETED MOLECULAR DOCKING ANALYSIS OF PYRAZOLE-CONDENSED HETEROCYCLICS AGAINST LUNG CANCER
Keywords:Lung cancer, pyrazolopyrimidines, pyrazolopyridines, molecular docking, pharmacophore modeling, anticancer activities.
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.
Prabhu VV, Devaraj N. Epidermal Growth Factor Receptor Tyrosine Kinase: A Potential Target in Treatment of Non-Small-Cell Lung Carcinoma. J Environ Pathol Toxicol Oncol. 2017; 36(2): 151-158. doi:10.1615/JEnvironPatholToxicolOncol. 2017018341.
Alferez D, Wilkinson RW, Watkins J, Poulsom R, Mandir N, Wedge SR, et al. Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in ApcMin/+ mice. Mol Cancer Ther. 2008;7(3):590-8.
Antonicelli A, Cafarotti S, Indini A, Galli A, Russo A, Cesario A, et al. EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci. 2013; 10(3): 320.
Castanon, E, Martín P, Rolf C, Fusco J P, Ceniceros L, Legaspi, et al. 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.
Jänne PA, Yang JCH, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et.al. AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer. N Engl J Med. 2015; 372(18): 1689-1699.
Gerber DE, Minna JD. ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. Cancer Cell. 2010; 18(6): 548-551.
Sang J, Acquaviva J, Friedland JC, Smith DL, Sequeira M, Zhang C, et.al. Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non–small cell lung cancer. Cancer discovery. 2013; 3(4): 430-443.
Nguyen-Ngoc T, Bouchaab H, Adjei A A, Peters S. BRAF alterations as therapeutic targets in non–small-cell lung cancer. J Thorac Oncol. 2015; 10(10): 1396-1403.
Gautschi O, Milia J, Cabarrou B, Bluthgen M V, Besse, B, Smit E F, et.al. Targeted therapy for patients with BRAF-mutant lung cancer results from the European EURAF cohort. J Thorac Oncol. 2015; 10(10): 1451-1457.
Feng Y, Hu J, Ma J, Feng K, Zhang X, Yang S, et.al. 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): 2353-2363.
Villaruz LC, Socinski MA. The role of anti-angiogenesis in non-small-cell lung cancer: an update. Curr. Oncol. Rep. 2015; 17(6): 26.
Yang J, Chen J, He J, Li J, Shi J, Cho WC. Wnt signaling as potential therapeutic target in lung cancer. Expert Opin Ther Targets. 2016; 20(8): 999-1015.
Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol. 2018; 12(1): 3-20.
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/genesandcancer.
Alevizako M, Kaltsas S, Syrigos KN. The VEGF pathway in lung cancer. Cancer Chemother Pharmacol. 2013, 72(6), 1169-1181. doi:10.1007/s00280-013-2298-3
Riffell JL, Lord CJ, Ashworth A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat Rev Drug discovery. 2012; 11(12): 923-936.
Santarpia M, Liguori A, Karachaliou N, Gonzalez-Cao M, Daffinà MG, D'Aveni A, et.al. Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy. Lung Cancer: Targets Ther. 2017; 8:109.
Descourt R, Perol M, Rousseau-Bussac G, Planchard D, Mennecier B, Wislez M, et.al. 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: 109-114.
Martinelli E, Troiani T, Morgillo F, Rodolico G, Vitagliano D, Morelli MP. Synergistic antitumor activity of sorafenib in combination with epidermal growth factor receptor inhibitors in colorectal and lung cancer cells. Clinical Cancer Res. 2010; 16(20): 4990-5001.
Shukla P, Sharma A, Fageria L, Chowdhury R. Novel spiro/nonspiro pyranopyrazoles: eco-friendly synthesis, in-vitro anticancer activity, DNA binding, and in-silico docking studies. Curr Bioact Compound. 2019; 15: 257–267. doi: 10.2174/1573407213666170828165512.
James JP, Bhat IK, Jose N. Synthesis, in silico physicochemical properties and biological activities of some pyrazoline derivatives. Asian J Pharm Clin Res. 2017;10(4): 456-9.
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.
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.
Salaheldin AM, Oliveira-Campos AM, Rodrigues LM. Heterocyclic synthesis with nitriles: synthesis of pyrazolopyrimidine and pyrazolopyridine derivatives. Synth Commun. 2009; 39(7): 1186-1195.
Schrodinger. Schrodinger Release 2019–4: https://www.schrodinger.com
PDB Database, https://www.rcsb.org/structure/4WKQ
Michellys PY, Chen B, Jiang T, Jin Y, Lu W, Marsilje TH, et.al. Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors. Bioorg Med Chem Lett. 2016; 26(3): 1090-1096.
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. Proceedings of the National Academy of Sciences. 2012; 109(45): 18281-18289.
Johannes JW, Almeida L, Barlaam B, Boriack-Sjodin PA, Casella RP, Croft RA, et.al. Pyrimidinone nicotinamide mimetics as selective tankyrase and wnt pathway inhibitors suitable for in vivo pharmacology. ACS Med Chem Lett. 2015; 6(3): 254-259.
Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein− ligand complexes. J Med Chem. 2006; 49(21): 6177-6196.
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: 3-26.
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. International Edition. 2016; 65 (2): 384-393. DOI: https://doi.org/10.1007/s11172-016-1310-6.
Francis D, Rita L. Rapid colorimetric assay for cell growth and survival: modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Method. 1986; 89: 271-277.
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 cyclising agent. Chem Cent J. 2018; 12: 64. https://doi.org/10.1186/s13065-018-0424-3.
Ismail NS, Ali EM, Ibrahim DA, Serya RA, Abou El Ella DA. Pyrazolo [3, 4-d] pyrimidine based scaffold derivatives targeting kinases as anticancer agents. Future Journal of Pharmaceutical Sciences. 2016; 2(1): 20-30.
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.
Chedid M, Eissa HO, Engler TA, Furness KW, Woods TA, Wrobleski AD. (2017). US Patent No. 9,624,218. Washington, DC: US Patent and Trademark Office.
Zhang J, Song Y, Liang Y, Zou H, Zuo P, Yan M, et al. Cucurbitacin IIa interferes with EGFR-MAPK signaling pathway leads to proliferation inhibition in A549 cells. Food Chem Toxicol. 2019 Oct 1;132:110654.
Prabhu VV, Elangovan P, Devaraj SN, 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.
Shi L, Zhang S, Wu H, Zhang L, Dai X, Hu J, et al. MiR-200c increases the radiosensitivity of non-small-cell lung cancer cell line A549 by targeting VEGF-VEGFR2 pathway. PloS one. 2013 Oct 30;8(10):e78344.
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 nonsmall-cell lung cancer. Tumor Biol. 2014 Oct;35(10):9759-67.
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.
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.
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Copyright (c) 2021 JAINEY P. JAMES, AISWARYA T. C., SNEH PRIYA, DIVYA JYOTHI, SHESHAGIRI R. DIXIT
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