Identification of Leads as Topoisomerase-II Inhibitors Using Pharmacophore Mapping
International Journal of Pharmacy and Chemistry
Volume 2, Issue 2, November 2016, Pages: 24-30
Received: Aug. 27, 2016; Accepted: Oct. 12, 2016; Published: Oct. 28, 2016
Views 3708      Downloads 211
Deveeka Zamare, Department of Biotechnology, Sreenidhi Institute of Science and Technology, Hyderabad, India
Shraddha Choudhary, Rajiv Gandhi Institute of IT and Biotechnology, Bharati Vidyapeeth University, Pune, India
Bishwambhar Mishra, Department of Biotechnology, Sreenidhi Institute of Science and Technology, Hyderabad, India
Article Tools
Follow on us
DNA topoisomerases are unique enzymes which play a major role in solving the topological problems associated with DNA molecule. Topoisomerase enzymes are highly expressed in cells which undergo rapid and uncontrolled cell divisions. Inhibition of this enzyme represents a major potential therapeutic approach for cancer. The computational tools that have allowed understanding the biological functions of Topoisomerase-II are being applied to understanding drug action. In this study, we have developed a quantitative pharmacophore model based on topoisomerase inhibitors collected from the literature. Molecular Docking Analysis was performed with AutoDock4 Software. Topoisomerase II (PDB-id 2RGR) was selected for finding its potent inhibitor. A comprehensive molecular modelling was performed to identify the pertinent features that could be used as a starting point for design of ligands with increased affinity and target selectivity. According to the pharmacophore mapping, the resulting pharmacophoric points could be used for the generation of new molecule that include all this point and hence will act as a better inhibitor for Topoisomerase II receptor.
Topoisomerases, Pharmacophore, Docking, Ligands
To cite this article
Deveeka Zamare, Shraddha Choudhary, Bishwambhar Mishra, Identification of Leads as Topoisomerase-II Inhibitors Using Pharmacophore Mapping, International Journal of Pharmacy and Chemistry. Vol. 2, No. 2, 2016, pp. 24-30. doi: 10.11648/j.ijpc.20160202.14
Copyright © 2016 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Bandgar, B.; Hote, B.; Gangwal, R.; Sangamwar, A: Synthesis, biological evaluation, and pharmacokinetic profiling of benzophenone derivatives as tumor necrosis factor-alpha and interleukin-6 inhibitors. Med. Chem. Rese. 2012, 21: 1-5.
Bohm, H. J.; Flohr, A.; Stahl, M: Scaffold hopping. Drug Discov Today Technol 2004, 1, 217–224, doi:10.1016/j.ddtec.2004.10.009
Dixon, S. L.; Smondyrev, A. M.; Knoll, E. H.; Rao, S. N.; Shaw, D.E.; Friesner, R.A: "PHASE: A New Engine for Pharmacophore Perception, 3D QSAR Model Development, and 3D Database Screening. Methodology and Preliminary Results, J. Comput. Aided Mol. Des. 2006, 20,647-671, doi:10.1007/s10822-006-9087-6.
Dixon, S. L.; Smondyrev, A. M.; Rao, S. N: PHASE: a novel approach to pharmacophore modeling and 3D database searching. Chem Biol Drug Des 2006. 67.370–372, doi: 10.1111/j.1747-0285.2006.00384.x.
Esteves-Souza A.; Claudio E.; Santos R.; Cistia CN.; Silva DR.; Carlos M R.; Sant Anna: Solvent-Free Synthesis, Glide, Schrödinger, LLC, New York, 2009; version 5.5.
Esteves-Souza, A.; Rodrigues-Santos, C. E.; Del Cistia, C. N.; Silva, D. R.; Sant'Anna, C. M. R.; Echevarria, A: Solvent-Free Synthesis,DNA-Topoisomerase II Activity and Molecular Docking Study of New Asymmetrically N,N'-Substituted Ureas. Molecules 2012; 17:12882-12894, doi:10.3390/molecules171112882.
Golbraikh, A.; Shen, M.; Xiao, Z.; Xiao, Y.D.; Lee, K. H.; Tropsha, A: Rational selection of training and test sets for the development of validated QSAR models. J. Comput. Aided Mol. Des 2003, 17,241-53.
Guner, O. F.; Henry, D. R: Development, and Use in Drug Design. La Jolla: IUL Biotechnology Series, 2000; First edition.
Irwin JJ, Shoichet BK; ZINC-a free database of commercially available compounds for virtual screening. J Chem Inf Mode 2005, 45,177–182, doi: 10.1021/ci049714+.
Jain, A. K.; Ravichandran, V. R.; Vaidya, A.; Mourya, V.; Agrawal, R.K: QSAR analysis of some novel sulphonamides incorporating 1, 3, 5-triazine derivatives as carbonic anhydrase inhibitors. Med. Chem. Rese. 2010, 19,1191-1202,doi:10.107/s00044-009-9262.0
Marriott, D. P.; Dougall, I. G.; Meghani, P.; Liu, Y.J.; Flower, D.R: Lead generation using pharmacophore mapping and three dimensional database searching: application to muscarinic M3 receptor antagonists. J.Med. Chem. 1999, 42,3210–3216, doi:10.1021/jm980409n
Mustata, G. I.; Brigo, A.; Briggs, J. M: HIV-1 integrase pharmacophore model derived from diverse classes of inhibitors. Bio. Med. Chem. Lett. 2004, 14, 1447–1454, doi.10.1016/j.bmcl.2004.01.027.
Naik, P. K.; Dubey, A.; Soni, K.; Kumar, R.; Singh, H: The binding modes and binding affinities of epipodophyllotoxin derivatives with human topoisomerase IIa. J. Mol. Graph. Model.2010, 29,546–564, doi:10.1016/j.jmgm.2010.10.005
Sordet, O.; Khan, Q. A.; Kohn, K. W.; Pommier, Y: Apoptosis induced by Topoisomerase Inhibitors. Curr. Med. Chem. Anticancer. Agent. 2003, 4, 271-290.
Teli, M. K.; Rajanikant, G. K: Identification of novel potential HIF-prolyl hydroxylase inhibitors by in silico screening. Molecular Diversity, 2012, 16,193–202.
Teli, MK.; Rajanikant, G. K: Pharmacophore generation and atom-based 3D-QSAR of N-iso-propyl pyrrole-based derivatives as HMG-CoA reductase inhibitors. Org. Med. Chem. Lett. 2012, 2, 25, doi:10.1007/s11030-011-9338-x.
Thapa, P.; Karki, R.; Choi, H.; Cho, J. H.; Lee, E.S: Synthesis of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives and evaluation of their topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship. Bio. Med. Chem. 2010, 18, 2245–2254.
Thapa, P.; Karki, R.; Thapa, U.; Yurngdong, J.; Lee, ES: 2Thienyl-4-furyl-6-aryl pyridine derivatives: Synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship study. Bio. Med. Chem. 2010; 18, 377–386.
Thapa, P.; Karki, R.; Yun, M.; Kadayat, T. M.; Lee, E.; Kwon, H.B.; Na, Y.; Cho, W.J.; Kim, N.D.; Jeong, B.S.; Kwon, Y.; Lee, E.S: Design, synthesis and antitumor evaluation of 2,4,6 triaryl pyridines containing chlorophenyl and phenolic moiety. Eur. J. Med. Chem. 2012, 52:123-136, doiI:10.1016/j.ejmech.2012.03.010.
Wang, J.C: Cellular roles of DNA topoisomerases. A molecular perspective. Nat. Rev. Mol. Cell Biol. 2002, 3,430-440, doi:10.1038/nrm831.
Wu, C. C.; Li, T. K; Farh, L.; Lin, L.Y.; Lin, T. S; Yu, Y. J.;Yen, T. J.; Chiang, CW; Chan, NL.: Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science 2011, 22, 333,459-62, doi:10.1126/science.1204117.
Yves Pommier: DNA Topoisomerase I Inhibitors. Chemistry, Biology and Interfacial Inhibition. Chemical Reviews. 2009, 109, 2894–2902, doi: 10.1021/cr900097c.
Yves Pommier: DNA Topoisomerases and Cancer. Humana Press, First Edition 2012.
Science Publishing Group
1 Rockefeller Plaza,
10th and 11th Floors,
New York, NY 10020
Tel: (001)347-983-5186