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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Molecular Docking of 4-ethoxychalcones on Oxidoreductase/Pirin Inhibitors and Cytotoxic Evaluation on Breast/Skin Cancer Cell Lines

Author(s): Kishori Ramachandra Harshitha, Balladka Kunhanna Sarojini*, Badiadka Narayana, Anupam Glorious Lobo and Bhuvanesh Sukhlal Kalal

Volume 17, Issue 10, 2020

Page: [1245 - 1260] Pages: 16

DOI: 10.2174/1570180817666200129143803

Price: $65

Abstract

Background: The role of α, β unsaturated propenone derivatives, has attracted the chemists for its biological importance. An attempt is made to reveal the interaction between breast and skin cancer cell lines with the help of molecular docking studies.

Objective: The study aimed to synthesize and characterize 4-ethoxychalcones for testing breast and skin cancer targets.

Methods: A series of chalcone analogues starting from 4-ethoxyacetophenone and substituted aromatic aldehydes were synthesized, well-characterized and evaluated for their in vitro anticancer activities against human breast cancer (MDA-MB-231) and human metastatic melanoma (A-375) cell lines by MTT assay. Docking simulation was performed to study the drug-receptor interaction of chalcone scaffold on the active site of target inhibitor bound to cytochrome P450 family oxidoreductase for breast cancer and Pirin inhibiting target for skin cancer, respectively.

Results and Discussion: After performing cytotoxic evaluation, it was observed that compounds having a substitution at the para position showed better results compared to ortho and meta positions for both the cell lines. Molecular docking studies revealed different types of interactions with selected oxidoreductase and Pirin inhibiting targets. Ligand-protein interactions and morphological changes are monitored by molecular dynamics.

Conclusion: The presence of electron-withdrawing and donating groups on ring B marginally affected IC50 and docking scores. The stability of the binding mode of ligands having high inhibitory efficiency for compounds 8 and 10 predicted by docking studies was confirmed by molecular dynamics simulation. The pharmacokinetic parameters were found to be within the acceptable range. Further molecular dynamics study would provide the necessary information.

Keywords: Chalcones, spectral characterization, cytotoxic evaluation, molecular docking, molecular dynamics simulations, pharmacokinetics.

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[1]
Das, M.; Manna, K. Chalcone scaffold in anticancer armamentarium: A molecular insight. J. Toxicol., 2016, 2016, 7651047.
[http://dx.doi.org/10.1155/2016/7651047] [PMID: 26880913]
[2]
Dhar, D.N. The chemistry of chalcones and related compounds, 1st ed; Wiley Interscience: New york, 1981.
[3]
Noorulla, K.M.; Suresh, A.J.; Devaraji, V.; Mathew, B.; Umesh, D. Molecular modeling of drug-pathophysiological Mtb protein targets: Synthesis of some 2-thioxo-1,3-thiazolidin-4-one derivatives as anti-tubercular agents. J. Mol. Struct., 2017, 1147, 682-696.
[http://dx.doi.org/10.1016/j.molstruc.2017.07.009]
[4]
Mathew, B.; Suresh, J.; Anbazhagan, S.; Paulraj, J.; Krishnan, G.K. Heteroaryl chalcones: Mini review about their therapeutic voyage. Biomed. Prev. Nut., 2014, 4, 451-458.
[http://dx.doi.org/10.1016/j.bionut.2014.04.003]
[5]
Gomes, M.N.; Muratov, E.N.; Pereira, M.; Peixoto, J.C.; Rosseto, L.P.; Cravo, P.V.L.; Andrade, C.H.; Neves, B.J. Chalcone derivatives: Promising starting points for drug design. Molecules, 2017, 22(8), 1210-1235.
[http://dx.doi.org/10.3390/molecules22081210] [PMID: 28757583]
[6]
Wu, M.L. Go.X.; Liu, X.L. Chalcones: An update on cytotoxic and chemoprotective properties. Curr. Med. Chem., 2005, 17, 483-499.
[7]
Holla, B.S.; Rao, B.S.; Sarojini, B.K.; Akberali, P.M. One pot synthesis of thiazolodihydropyrimidinones and evaluation of their anticancer activity. Eur. J. Med. Chem., 2004, 39(9), 777-783.
[http://dx.doi.org/10.1016/j.ejmech.2004.06.001] [PMID: 15337290]
[8]
Salian, V.V.; Narayana, B.; Sarojini, B.K.; Sindhupriya, E.S.; Madhu, L.N.; Rao, S. Biologically potent pyrazoline derivatives from versatile (2E)-1-(4-chlorophenyl)-3-[4-(propan-2- yl)phenyl]prop-2-en-1-one. Lett. Drug Des. Discov., 2016, 13, 1-8.
[9]
Samshuddin, S.; Narayana, B.; Sarojini, B.K.; Khan, M.T.H.; Yathirajan, H.S.; Darshanraj, C.G.; Raghavendra, R. Antimicrobial, analgesic, DPPH scavenging activities and molecular docking study of some 1, 3, 5-triaryl-2-pyrazolines. Med. Chem. Res., 2012, 21, 2012-2022.
[http://dx.doi.org/10.1007/s00044-011-9735-9]
[10]
Baktır, Z.; Akkurt, M.; Samshuddin, S.; Narayana, B.; Yathirajan, H.S. 2,4-Bis(4-fluorophenyl)-2,3-dihydro-1H-1,5-benzodiazepine. Acta Crystallogr., 2011, E67, o1262-o1263.
[11]
Baktır, Z.; Akkurt, M.; Samshuddin, S.; Narayana, B.; Yathirajan, H.S. 3, 5-Bis (4-fluorophenyl)-4, 5-dihydro-1H-pyrazole-1-carbaldehyde. Acta Crystallogr., 2011, E67, o1292-o1293.
[12]
Samshuddin, S.; Narayana, B.; Shetty, D.N.; Raghavendra, R. An efficient synthesis of 2, 4, 6-triaryl pyridines and their biological evaluation. Pharma Chem., 2011, 3, 232-240.
[13]
Harrison, W.T.A.; Yathirajan, H.S.; Anilkumar, H.G.; Sarojini, B.K.; Narayana, B. 1-(4-Fluorophenyl)-3-(4-methoxyphenyl) prop-2-en-1-one. Acta Crystallogr., 2006, E62, o3251-o3253.
[14]
Fun, H.K.; Hemamalini, M.; Samshuddin, S.; Narayana, B.; Sarojini, B.K. 1-(4, 4′′-Difluoro-5′-methoxy-1, 1′: 3′, 1′′-terphenyl-4′-yl) ethanone. Acta Crystallogr., 2012, E68, o163-o163.
[15]
Sreevidya, T.V.; Narayana, B.; Yathirajan, H.S. Synthesis and characterization of some chalcones and their cyclohexenone derivatives. Open Chem., 2010, 8, 174-181.
[http://dx.doi.org/10.2478/s11532-009-0124-x]
[16]
Gacche, R.; Khsirsagar, M.; Kamble, S.; Bandgar, B.; Dhole, N.; Shisode, K.; Chaudhari, A. Antioxidant and anti-inflammatory related activities of selected synthetic chalcones: structure-activity relationship studies using computational tools. Chem. Pharm. Bull. (Tokyo), 2008, 56(7), 897-901.
[http://dx.doi.org/10.1248/cpb.56.897] [PMID: 18591798]
[17]
Darshanraj, C.G.; Sarojini, B.K.; Ramakrishna, M.K.; Ramesh, S.R.; Manjunatha, H. In vivo peritoneal antiangiogenesis and in vitro antiproliferative properties of some bischalcone derivatives. Med. Chem. Res., 2012, 21, 453-458.
[http://dx.doi.org/10.1007/s00044-011-9551-2]
[18]
Bandgar, B.P.; Gawande, S.S.; Bodade, R.G.; Totre, J.V.; Khobragade, C.N. Synthesis and biological evaluation of simple methoxylated chalcones as anticancer, anti-inflammatory and antioxidant agents. Bioorg. Med. Chem., 2010, 18(3), 1364-1370.
[http://dx.doi.org/10.1016/j.bmc.2009.11.066] [PMID: 20064725]
[19]
Rao, Y.K.; Fang, S.H.; Tzeng, Y.M. Differential effects of synthesized 2′-oxygenated chalcone derivatives: Modulation of human cell cycle phase distribution. Bioorg. Med. Chem., 2004, 12(10), 2679-2686.
[http://dx.doi.org/10.1016/j.bmc.2004.03.014] [PMID: 15110849]
[20]
(a) Butcher, R.J.; Yathirajan, H.S.; Narayana, B.; Mithun, A.; Sarojini, B.K. 2E)-1-(2, 4-Dichlorophenyl)-3-[4-(methylsulfanyl) phenyl] prop-2-en-1-one. Acta Crystallogr., 2007.
(b) Yathirajan, H.S.; Sarojini, B.K.; Narayana, B.; Bindya, S.; Bolte, M. 2E)-1-(2, 4-Dichlorophenyl)-3-[4-(methylsulfanyl) phenyl] prop-2-en-1-one. Acta Crystallogr., 2006.
(c) Butcher, R.J.; Yathirajan, H.S.; Mithun, A.; Narayana, B.; Sarojini, B.K. Chalcone and its hydroxobromo derivative: a 1: 1 mixed crystal containing chalcone and 2- bromo3-hydroxy-1-(4-methylphenyl)-3-[4-(methylsulfanyl) phenyl] propan-1-one. Acta Crystallogr., 2006, E62, o2350-o2352.
[21]
Release, S. 2015-1: Desmond Molecular Dynamics System, version, 4.1; D.E. Shaw Research: New York, 2015.
[22]
Dong, J.; Zhang, Q.; Cui, Q.; Huang, G.; Pan, X.; Li, S. Flavonoids and naphthoflavonoids: Wider roles in the modulation of cytochrome P450 family 1 enzymes. ChemMedChem, 2016, 11(19), 2102-2118.
[http://dx.doi.org/10.1002/cmdc.201600316] [PMID: 27551833]
[23]
Riddick, D.S.; Ding, X.; Wolf, C.R.; Porter, T.D.; Pandey, A.V.; Zhang, Q.Yu.; Gu, J.; Finn, R.D.; Ronseaux, S.; McLaughlin, L.A.; Henderson, C.J.; Zou, L.; Flück, C.E. NADPH-cytochrome P450 oxidoreductase: Roles in physiology, pharmacology, and toxicology. Drug Metab. Dispos., 2013, 41(1), 12-23.
[http://dx.doi.org/10.1124/dmd.112.048991] [PMID: 23086197]
[24]
Miyazaki, I.; Simizu, S.; Okumura, H.; Takagi, S.; Osada, H. A small-molecule inhibitor shows that pirin regulates migration of melanoma cells. Nat. Chem. Biol., 2010, 6(9), 667-673.
[http://dx.doi.org/10.1038/nchembio.423] [PMID: 20711196]
[25]
Licciulli, S.; Luise, C.; Scafetta, G.; Capra, M.; Giardina, G.; Nuciforo, P.; Bosari, S.; Viale, G.; Mazzarol, G.; Tonelli, C.; Lanfrancone, L.; Alcalay, M. Pirin inhibits cellular senescence in melanocytic cells. Am. J. Pathol., 2011, 178(5), 2397-2406.
[http://dx.doi.org/10.1016/j.ajpath.2011.01.019] [PMID: 21514450]
[26]
Adams, M.; Jia, Z. Structural and biochemical analysis reveal pirins to possess quercetinase activity. J. Biol. Chem., 2005, 280(31), 28675-28682.
[http://dx.doi.org/10.1074/jbc.M501034200] [PMID: 15951572]
[27]
Harshitha, K.R.; Sarojini, B.K.; Narayana, B.; Lobo, A.G.; Madan, S.K.; Byrappa, K. Single crystal X-ray studies and Hirshfeld surface analysis of ethoxy phenyl substituted chalcone derivatives. Chemical Data Collections., 2018, 17, 121-131.
[http://dx.doi.org/10.1016/j.cdc.2018.08.002]
[28]
Wang, A.; Savas, U.; Stout, C.D.; Johnson, E.F. Structural characterization of the complex between alpha-naphthoflavone and human cytochrome P450 1B1. J. Biol. Chem., 2011, 286(7), 5736-5743.
[http://dx.doi.org/10.1074/jbc.M110.204420] [PMID: 21147782]
[29]
Hunter, C.A.; Sanders, J.K.M. The Nature of π-π Interactions. J. Am. Chem. Soc., 1990, 112, 5525-5534.
[http://dx.doi.org/10.1021/ja00170a016]
[30]
Shoichet, B.K.; McGovern, S.L.; Wei, B.; Irwin, J.J. Lead discovery using molecular docking. Curr. Opin. Chem. Biol., 2002, 6(4), 439-446.
[http://dx.doi.org/10.1016/S1367-5931(02)00339-3] [PMID: 12133718]
[31]
Gschwend, D.A.; Good, A.C.; Kuntz, I.D. Molecular docking towards drug discovery. J. Mol. Recognit., 1996, 9(2), 175-186.
[http://dx.doi.org/10.1002/(SICI)1099-1352(199603)9:2<175::AID-JMR260>3.0.CO;2-D] [PMID: 8877811]
[32]
Safarizadeh, H.; Garkani-Nejad, Z. Molecular docking, molecular dynamics simulations and QSAR studies on some of 2-arylethenylquinoline derivatives for inhibition of Alzheimer’s amyloid-beta aggregation: Insight into mechanism of interactions and parameters for design of new inhibitors. J. Mol. Graph. Model., 2019, 87, 129-143.
[http://dx.doi.org/10.1016/j.jmgm.2018.11.019] [PMID: 30537643]
[33]
Bellini, R.G.; Coronado, M.A.; Paschoal, A.R.; Gaudencio do Rêgo, T.; Hungria, M.; Ribeiro de Vasconcelos, A.T.; Nicolás, M.F. Structural analysis of a novel N-carbamoyl-d-amino acid amidohydrolase from a Brazilian Bradyrhizobium japonicum strain: In silico insights by molecular modelling, docking and molecular dynamics. J. Mol. Graph. Model., 2019, 86, 35-42.
[http://dx.doi.org/10.1016/j.jmgm.2018.10.005] [PMID: 30336451]

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