Design and docking of novel series of hybrid xanthones as anti-cancer agent to target human DNA topoisomerase 2-alpha

Authors

  • Lalit Mohan Nainwal Department of Pharmaceutical Sciences, Dibrugarh University
  • Pratap Parida Bioinformatics Infrastructure Facility, Centre for Studies in Biotechnology, Dibrugarh University, Assam-786004, India.
  • Aparoop Das Department of Pharmaceutical Sciences, Dibrugarh University
  • Parth Sarathi Bairy Department of Pharmaceutical Sciences, Dibrugarh University

DOI:

https://doi.org/10.3329/bjp.v9i2.18180

Keywords:

ADMET, Docking, Homology modeling, Hybrid xanthone, Topoisomerase II-alpha

Abstract

Topoisomerase (topo) IIα is a homodimeric protein catalyzes topological vicissitudes by adding or by soothing super coiling transpiration, occurs in human DNA during DNA replication as an outcome chromosome segregation and condensation occurs during meiosis I and recombination. To prevent the cleavage and religation activity we administered novel hybrid substituted Xanthone series of drugs. The toxicity prediction showed outstanding results which impetus to study its anticancer activities by targeting topoisomerase (topo) IIα. We developed the homology model of the topoisomerase (topo) IIα due to the unavailability of 3D structure in the Protein Data Bank. Structural assessment of the modeled protein and confirmed the quality of the model. The ligands were docked using Autodock4.2 software and binding energy was reported. The compound XM9, XN2, XM7, XLNU and XNS scored lowest binding energy and highest binding affinity. The interaction sites and the hydrogen bond were observed.

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References

Bailly C. Contemporary challenges in the design of Topoisomerase II inhibitors for cancer chemotherapy. Chem Rev. 2012; 112: 3611-40.

Binaschi M, Bigioni M, Cipollone A, Rossi C, Goso C, Maggi CA, Capranico G, Animati F. Anthracyclines: Selected new developments. Curr Med Chem Anti-cancer Agents. 2001; 1: 113-30.

Boehm HJ, Boehringer M, Bur D, Gmuender H, Huber W, Klaus W, Kostrewa D, Kuehne H, Luebbers T, Meunier-Keller N, Mueller F. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. J Med Chem. 2000; 43: 2664-74.

Champoux JJ. DNA topoisomerases: Structure, function, and mechanism. Annu Rev Biochem. 2001; 70: 369-413.

Dong KC, Berger JM. Structural basis for gate-DNA recognition and bending by type IIA topoisomerases. Nature 2007; 450: 1201-05.

Fortune JM, Prog ON. Topoisomerase II as a target for anti-cancer drugs: When enzymes stop being nice. Prog Nucleic Acid Res Mol Biol. 2000; 64: 221-53.

Heck MM, Earnshaw WC. Topoisomerase II: A specific marker for cell proliferation. J Cell Biol. 1986; 103: 2569-81.

Hu CX, Zuo ZL, Xiong B, Ma JG, Geng MY, Lin LP, Jiang HL, Ding J. Salvicine functions as novel topoisomerase II poison by binding to ATP pocket. Mol Pharmacol. 2006; 70: 1593-601.

Jun KY, Lee EY, Jung MJ, Lee OH, Lee ES, Park Choo HY, Na Y, Kwon Y. Synthesis, biological evaluation, and molecular docking study of 3-(30-heteroatom substituted-20-hydroxy-10-propyloxy) xanthone analogues as novel Topoisomerase IIa catalytic inhibitor. Eur J Med Chem. 2011; 46: 1964-71.

Larsen AK, Escargueil AE, Skladanowski A. Catalytic topoisomerase II inhibitors in cancer therapy. Pharmacol Ther. 2003; 99: 167-81.

Liu LF. DNA topoisomerase poisons as antitumor drugs. Ann Rev Biochem. 1989; 58: 351-75.

Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009; 9: 338-50.

Patil TD, Thakare SV. In silico evaluation of selected triterpene glycosides as a human DNA topoisomerase II alpha (α) inhibitor. Int J Pharm Pharm Sci. 2012; 4: 201-04.

Robinson MJ, Osheroff N. Effects of antineoplastic drugs on the poststrand-passage DNA cleavage/religation equilibrium of topoisomerase II. Biochemistry 1991; 30: 1807-13.

Shen R, Wang P, Tang N. Cytotoxic Activity and DNA-binding Properties of Xanthone Derivatives. J Fluoresc. 2010; 20: 1287-97.

Su QG, Liu Y, Cai YC, Sun YL, Wang B, Xian LJ. Anti-tumour effects of xanthone derivatives and the possible mechanisms of action. Invest New Drugs. 2011; 29: 1230-40.

Vilain N, Tsai-Pflugfelder M, Benoit A, Gasser SM, Leroy D. Modulation of drug sensitivity in yeast cells by the TP-binding domain of human DNA topoisomerase IIa. Nucleic Acids Res. 2003; 31: 5714-22.

Watt PM, Hickson ID. Structure and function of type II DNA topoisomerases. Biochem J. 1994; 303: 681-95.

Wilstermann AM, Osheroff N. Stabilization of eukaryotic topoisomerase II-DNA cleavage complexes. Curr Top Med Chem. 2003; 3: 321-38.

Woessner RD, Mattern MR, Mirabelli CK, Johnson RK, Drake FH. Proliferation- and cell cycle-dependent differences in expression of the 170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3T3 cells. Cell Growth Differ. 1991; 2: 209-14.

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Published

2014-05-05

How to Cite

Nainwal, L. M., P. Parida, A. Das, and P. S. Bairy. “Design and Docking of Novel Series of Hybrid Xanthones As Anti-Cancer Agent to Target Human DNA Topoisomerase 2-Alpha”. Bangladesh Journal of Pharmacology, vol. 9, no. 2, May 2014, pp. 208-17, doi:10.3329/bjp.v9i2.18180.

Issue

Vol. 9 No. 2 (2014)

Section

Research Articles

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