Research Article
Year 2019,
Volume: 6 Issue: 1, 71 - 78, 15.05.2019
Abstract
DNA
topoisomerases are proved therapeutic targets of anticancer and antibacterial
drugs. Structures of
topoisomerase–DNA and inhibitor ternary complexes have revealed the exact
binding sites and mechanisms of topoisomerase poisons. There are two isoforms
of Human Topoisomerase II; α and β. Both of them perform similar functions and
their levels differ depending on the replicative activity and type of tissue.
Topo IIα is preferentially expressed in proliferating cells. Thus selective
Topo IIα inhibitors have been of particular interest in cancer therapy, as they
may represent a more targeted approach to highly proliferative cells.
In this
study, we use structure based virtual screening method with molecules which are
commercially available in the ZINC database. Docking studies were performed by
Glide module available in Schrödinger software, Ligand filtration was also done
to obtain an efficient collection of hit molecules by employing Lipinski “rule
of five” and pharmacokinetic properties of the compounds were tested using
Qikprop module. From approximately ten thousand compounds from Zinc database
it was possible to select 4 top chemical structures with good inhibiting
profile for topo II, with suitable ADME/Tox properties, thus comp. 1-4 could be
the promising inhibitors of human topo IIα enzyme.
References
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- 11. Diniz EMLP, Poiani JGC, Taft CA, da Silva CHTP. Structure-Based Drug Design, Molecular Dynamics and ADME/Tox to Investigate Protein Kinase Anti-Cancer Agents. Curr. Bioact. Comp. 2017, 13(3):213–22.
- 12. Verma P, Tiwari M, Tiwari V. In silico high-throughput virtual screening and molecular dynamics simulation study to identify inhibitor for AdeABC efflux pump of Acinetobacter baumannii. J Biomol. Struct. Dyn. 2018, 36(5):1182-94.
- 13. Taft CA, da Silva CHTP. Current State-of-the-art for Virtual Screening and Docking Methods New Developments in Medicinal Chemistry, Bentham Science: Dubai, 2014, (2):3-169.
- 14. Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM. The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. J. Mol. Biol. 2012, (424):109−24.
- 15. Wang YR, Chen SF, Wu CC, Liao YW, Lin TS, Liu KT, Chen YS, Li TK, Chien TC, Chan NL. Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt (II)-methionine coordination chemistry. Nucleic Acids Res. 2017, (45):10861-71.
- 16. Friesner RA, Banks JI, Murphy RB, Halgren TA, Kicic JJ, Maung DAT, Repasky MP, Knowll EH. Glide: A new approach for rapid, accurate docking and scoring: Method and assessment of docking accuracy. J. Med. Chem. 2004, (47):1739-49.
- 17. Schrödinger LLC. New York, USA: Schrodinger Inc.; 2008. http://www.schrodinger.com
- 18. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT. Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes, J. Med. Chem. 2006, (49):6177–96.
- 19. Schrödinger Release 2018-2: QikProp, Schrödinger, LLC, New York, NY, 2018.
- 20. 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 Deliv Rev. 2012, 64(1‑3):4‑17.
Year 2019,
Volume: 6 Issue: 1, 71 - 78, 15.05.2019
Abstract
References
- 1. Wang JC. Cellular roles of DNA topoisomerases: A molecular perspective. Nat. Rev. Mol. Cell Biol. 2002, (3):430−40.
- 2. Cowell IG, Sondka Z, Smith K, Lee KC, Manville CM, Sidorczuk-Lesthuruge M, Rance HA, Padget K, Jackson GH, Adachi N, Austin CA. Model for MLL translocations in the rapyrelated leukemia involving topoisomerase II β-mediated DNA strand breaks and gene proximity. Proc. Natl. Acad. Sci. U. S. A. 2012, (109):8989−94.
- 3. Nitiss JL. DNA topoisomerase II and its growing repertoire of biological functions. Nat. Rev. Cancer. 2009, (9):327−33.
- 4. Tiwari VK, Burger L, Nikoletopoulou V, Deogracias R, Thakurela S, Wirbelauer C, Kaut J, Terranova R, Hoerner L, Mielke C, Boege F, Murr R, Peters AH, Barde YA, Schübeler D. Target genes of topoisomerase II β regulate neuronal survival and are defined by their chromatinstate. Proc.Natl.Acad.Sci.U.S.A. 2012, (109):E934−43.
- 5. Pogorelcnik B, Perdih A, Solmajer T. Recent advances in the development of catalytic inhibitors of human DNA topoisomerase IIα as novel anticancer agents. Curr. Med. Chem. 2013, 20(5):694-709.
- 6. Schmidt, B.H.; Osheroff, N.; Berger, J.M. Structure of a topoisomerase II-DNA-nucleotide complex reveals a new control mechanism for ATPase activity. Nat. Struct. Mol. Biol., 2012, 19(11): 1147-54.
- 7. Larsen AK, Escargueil AE, Skladanowski A. Catalytic topoisomerase II inhibitors in cancer therapy. Pharmacol. Ther. 2003, (99):167−81.
- 8. Farr CJ, Antoniou-Kourounioti M, Mimmack ML, Volkov A, Porter AC. The α isoform of topoisomerase II is required for hyper compaction of mitotic chromosomes in human cells. Nucleic Acids Res. 2014, (42):4414−26.
- 9. D’Arcy N, Gabrielli B. Topoisomerase II Inhibitors and Poisons, and the Influence of Cell Cycle Checkpoints. Curr. Med. Chem. 2017, (24):1504-19.
- 10. McClendon, A. K.; Rodriguez, A. C.; Osheroff, N. Human topoisomerase IIalpha rapidly relaxes positively supercoiled DNA: implications for enzyme action ahead of replication forks. J.Biol.Chem. 2005, (280):39337−45.
- 11. Diniz EMLP, Poiani JGC, Taft CA, da Silva CHTP. Structure-Based Drug Design, Molecular Dynamics and ADME/Tox to Investigate Protein Kinase Anti-Cancer Agents. Curr. Bioact. Comp. 2017, 13(3):213–22.
- 12. Verma P, Tiwari M, Tiwari V. In silico high-throughput virtual screening and molecular dynamics simulation study to identify inhibitor for AdeABC efflux pump of Acinetobacter baumannii. J Biomol. Struct. Dyn. 2018, 36(5):1182-94.
- 13. Taft CA, da Silva CHTP. Current State-of-the-art for Virtual Screening and Docking Methods New Developments in Medicinal Chemistry, Bentham Science: Dubai, 2014, (2):3-169.
- 14. Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM. The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. J. Mol. Biol. 2012, (424):109−24.
- 15. Wang YR, Chen SF, Wu CC, Liao YW, Lin TS, Liu KT, Chen YS, Li TK, Chien TC, Chan NL. Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt (II)-methionine coordination chemistry. Nucleic Acids Res. 2017, (45):10861-71.
- 16. Friesner RA, Banks JI, Murphy RB, Halgren TA, Kicic JJ, Maung DAT, Repasky MP, Knowll EH. Glide: A new approach for rapid, accurate docking and scoring: Method and assessment of docking accuracy. J. Med. Chem. 2004, (47):1739-49.
- 17. Schrödinger LLC. New York, USA: Schrodinger Inc.; 2008. http://www.schrodinger.com
- 18. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT. Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes, J. Med. Chem. 2006, (49):6177–96.
- 19. Schrödinger Release 2018-2: QikProp, Schrödinger, LLC, New York, NY, 2018.
- 20. 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 Deliv Rev. 2012, 64(1‑3):4‑17.
There are 20 citations in total.
Details
| Primary Language | English |
|---|---|
| Subjects | Chemical Engineering |
| Journal Section | Articles |
| Authors | |
| Publication Date | May 15, 2019 |
| Submission Date | October 2, 2018 |
| Acceptance Date | February 5, 2019 |
| Published in Issue | Year 2019 Volume: 6 Issue: 1 |
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