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Computational study of curcumin analogues by targeting DNA topoisomerase II: a structure-based drug designing approach

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Abstract

Curcumin, a golden yellow pigment present in the spice turmeric, has pleiotropic chemopreventive and therapeutic active compound against many diseases including cancer. It has been reported that curcumin acts as a topoisomerase II inhibitor and it was found that even concentration of 50 µM of curcumin in vitro is active in a similar fashion as etoposide (antineoplastic agent). Topoisomerases (type I and type II) are enzymes that regulate the overwinding or underwinding of DNA by cutting the phosphate bond of one or two strands of DNA, respectively. Topoisomerase II was selected as target, since it affects both strands of DNA. The present in silico study about designing curcumin analogues as better inhibitors of topoisomerase vis-à-vis curcumin is based on ADME filtering and docking simulation using Schrödinger suite. The docking simulation result suggested that out of 1000 designed curcumin analogues using ligbuilder tool and curcumin as a lead, 293 screened analogues show good binding affinity at the active site of Human DNA topoisomerase II in comparison to known drug Salvicine. The top five analogues with best binding affinity was shown by ligand1_826, ligand1_758, ligand1_976, ligand1_956 and ligand1_827 with glide scores − 16.70, − 16.03, − 15.45, − 15.43 and − 15.09, respectively. Therefore it is possible that screened curcumin analogues can be used as lead molecules for screening of ligand database and future chemopreventive agents.

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References

  • ACD/ChemSketch version 8.0 (2006) Advanced Chemistry Development, Inc., Toronto ON, canada, http://www.acdlabs.com. Accessed 5 July 2014

  • Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23(1A):363–398

    Google Scholar 

  • Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242

    Article  Google Scholar 

  • Bharti AC, Donato N, Singh S, Aggarwal BB (2003) Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and Ikappa B alpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 101(3):1053–1062

    Article  Google Scholar 

  • Bradley G, Juranka PF, Ling V (1988) Mechanism of multidrug resistance. Biochim Biophys Acta 948(1):87–128

    Google Scholar 

  • Cattan AR, Levett D, Douglas EA, Middleton PG, Taylorm PR (1996) Method for quantifying expression of functionally active topoisomerase II in patients with leukaemia. J Clin Pathol 49(10):848–852

    Article  Google Scholar 

  • Chao-Xin H, Zhi-Li Z, Bing X, Jin-Gui M, Mei-Yu G, Li-Ping L, Hua-Liang J, Jian D (2006) Salvicine functions as novel topoisomerase II poison by binding to ATP pocket. Mol Pharmacol 70:1593–1601

    Article  Google Scholar 

  • Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 49:6177–6196

    Article  Google Scholar 

  • Gadakar PK, Phukan S, Dattatreya P, Balaji VN (2007) Pose prediction accuracy in docking studies and enrichment of actives in the active site of GSK-3β. J Chem Inf Model 47:1446–1459

    Article  Google Scholar 

  • Halgren T (2009) Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model 49:377–389

    Article  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  Google Scholar 

  • Holy JM (2002) Curcumin disrupts mitotic spindle structure and induces micronucleation in MCF-7 breast cancer cells. Mutation Res 518(1):71–84

    Article  Google Scholar 

  • Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    Article  Google Scholar 

  • Karunagaran D, Rashmi R, Kumar TR (2005) Induction of apoptosis by curcumin and its implications for cancer therapy. Curr Cancer Drug Targets 5(2):117–129

    Article  Google Scholar 

  • Keserwani RK, Kesharwani RK, Vyas N, Jain S, Raghuvanshi R, Sharma AK (2010a) Nutraceutical and functional food as future food: a review. Der Pharmacia Lettre 2010: 2(1):106–116

    Google Scholar 

  • Keserwani RK, Kesharwani RK, Vyas N, Chadokar A (2010b) Nutritional supplements: an overview. Int J Curr Pharm Rev Res 1(1):59–75

    Google Scholar 

  • Kesharwani RK, Misra K (2011) Prediction of binding site for curcuminoids at human topoisomerase II α protein; an in silico approach. Curr Sci 101(8):1060–1064

    Google Scholar 

  • Kesharwani RK, Singh DV, Misra K (2013) Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach. J Vector Borne Dis 50:93–102

    Google Scholar 

  • Kesharwani RK, Srivastava V, Singh P, Rizvi SI, Adeppa K, Misra K (2015) A novel approach for overcoming drug resistance in breast cancer chemotherapy by targeting new synthetic curcumin analogues against aldehyde dehydrogenase 1 (ALDH1A1) and glycogen synthase kinase-3 β (GSK-3β). Appl Biochem Biotechnol. https://doi.org/10.1007/s12010-015-1696-x

    Article  Google Scholar 

  • Maestro (v7.0.113) (2005) A unified interface for all Schrodinger products, developed and marketed by Schrodinger, LLC. NY http://www.schrodinger.com. Accessed 5 July 2014

  • Martín-Cordero C, López-Lázaro M, Gálvez M, Ayuso MJ (2003) Curcumin as a DNA topoisomerase II poison. J Enzyme Inhib Med Chem18(6):505–509

    Article  Google Scholar 

  • Martin-Richard M, Muñoz M, Albanell J, Colomo L, Bellet M, Rey MJ, Tabernero J, Alonso C, Cardesa A, Gascon P, Fernandez PL (2004) Serial topoisomerase II expression in primary breast cancer and response to neoadjuvant anthracycline-based chemotherapy. Oncology 66(5):388–394

    Article  Google Scholar 

  • McDonald IK, Thornton JM (1994) Satisfying hydrogen bonding potential in proteins. JMB 238:777–793

    Article  Google Scholar 

  • Mueller-Planitz F, Herschlag D (2007) DNA topoisomerase II selects DNA cleavage sites based on reactivity rather than binding affinity. Nucleic Acids Res 35(11):3764–3773

    Article  Google Scholar 

  • Poma P, Notarbartolo M, Labbozzetta M, Maurici A, Carina V, Alaimo A et al (2007) The antitumor activities of curcumin and of its isoxazole analogue are not affected by multiple gene expression changes in an MDR model of the MCF-7 breast cancer cell line: analysis of the possible molecular basis. Int J Mol Med 20(3):329–335

    Google Scholar 

  • Ravindran J, Prasad S, Aggarwal BB (2009) Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J 11(3):495–510

    Article  Google Scholar 

  • Ruby AJ, Kuttan G, Dinesh Babu K, Rajasekharan KN, Kuttan R (1995) Anti-tumour and antioxidant activity of natural curcuminoids. Cancer Lett 94(1):79–83

    Article  Google Scholar 

  • Singh DB, Gupta MK, Kesharwani RK, Misra K (2013) Comparative docking and ADMET study of some curcumin derivatives and herbal congeners targeting b-amyloid. Netw Model Anal Health Inform Bioinform (2013) 2:13–27. https://doi.org/10.1007/s13721-012-0021-7

    Article  Google Scholar 

  • Singh DV, Agarwal S, Kesharwani RK, Misra K (2014) 3D QSAR and pharmacophore study of curcuminoids and curcumin analogs: interaction with thioredoxin reductase, interdisciplinary sciences. Comput Life Sci 5(4):286–295

    Google Scholar 

  • Singh P, Kesharwani RK, Misra K, Rizvi SI (2015) The modulation of erythrocyte Na+/K+-ATPase activity by curcumin. J Adv Res. https://doi.org/10.1016/j.jare.2014.12.007

    Article  Google Scholar 

  • Sun A, Lu YJ, Hu H, Shoji M, Liotta DC, Snyder JP (2009) Curcumin analog cytotoxicity against breast cancer cells: exploitation of a redox-dependent mechanism. Bioorg Med Chem Lett 19(23):6627–6631. https://doi.org/10.1016/j.bmcl.2009.10.023

    Article  Google Scholar 

  • Thomsen R, Christensen MH (2006) MolDock: a new technique for high-accuracy molecular docking. J Med Chem 49(11):3315–3321

    Article  Google Scholar 

  • Tripathi A, Singh DV, Kesharwani RK, Misra K (2014) P-Glycoprotein: a critical comparison of models depicting mechanism of drug efflux and role of modulators. Proc Natl Acad Sci India Sect B Biol. https://doi.org/10.1007/s40011-014-0405-9

    Article  Google Scholar 

  • Upadhyay J, Kesharwani RK, Misra K (2009) Comparative study of antioxidants as cancer preventives through inhibition of HIF-1 alpha activity. Bioinformation 4(6):233–236

    Article  Google Scholar 

  • Upadhyaya J, Kesharwani RK, Misra K (2009) Metabolism, pharmacokinetics and bioavailability of ascorbic acid; synergistic effect with tocopherols and curcumin. J Comput Intell Bioinform 2(1):77–84

    Google Scholar 

  • Wang JC (2002) Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3(6):430–440

    Article  Google Scholar 

  • Wang R, Gao Y, Lai L (2000) Ligbuilder: a multiple-purpose program for structure-based drug design. J Mol Model 6:498–516

    Article  Google Scholar 

  • Waris G, Ahsan H (2006) Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog 5:14

    Article  Google Scholar 

  • Wei H, Ruthenburg AJ, Bechis SK, Verdine GL (2005) Nucleotide-dependent domain movement in the ATPase domain of a human type IIA DNA topoisomerase. J Biol Chem 280(44):37041–37047

    Article  Google Scholar 

Download references

Acknowledgements

Rajesh Kr. Kesharwani acknowledge the support of Indian council of medical research (ICMR), New Delhi, India for providing Senior Research Fellowship.

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Authors and Affiliations

  1. Department of Advanced Science and Technology, NIET, Nims University Rajasthan, Jaipur, 303121, India

    Rajesh Kumar Kesharwani

  2. Department of Biotechnology, Institute of Biosciences and Biotechnology, Chhatrapati Shahu Ji Maharaj University, Kanpur, Uttar Pradesh, 208024, India

    Dev Bukhsh Singh

  3. Department of Bioinformatics, Central University of Bihar, Patna, India

    Durg Vijay Singh

  4. Division of Applied Science and IRCB, Indian Institute of Information Technology, Allahabad, Uttar Pradesh, 211012, India

    Krishna Misra

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  1. Rajesh Kumar Kesharwani
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Correspondence to Rajesh Kumar Kesharwani.

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Kesharwani, R.K., Singh, D.B., Singh, D.V. et al. Computational study of curcumin analogues by targeting DNA topoisomerase II: a structure-based drug designing approach. Netw Model Anal Health Inform Bioinforma 7, 15 (2018). https://doi.org/10.1007/s13721-018-0179-8

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  • DOI: https://doi.org/10.1007/s13721-018-0179-8

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