Skip to main content

Advertisement

SpringerLink
Log in

Exploring the binding mode of triflamide derivatives at the active site of Topo I and Topo II enzymes: In silico analysis and precise molecular docking

  • Regular Article
  • Published:
Journal of Chemical Sciences Aims and scope Submit manuscript

In honor of my father Leonardo Andrade Capetillo.

Abstract

The DNA topoisomerase enzymes, Topo I and Topo II, have been used as molecular targets for drug design of anticancer agents. The search is for new anticancer therapies that respond to the toxicity of current drug treatments and tumor resistance. The present study provides insights into a likely dual inhibitory effect on Topo I and II of trifluoromethylsulfonamide (triflamide) derivatives by computational docking studies. The physicochemical properties of these compounds were evaluated by Lipinski’s rules. Molecular docking simulations were conducted to determine the possible molecular target, mode and energy binding of the triflamide derivatives. An in silico analysis indicated that the triflamide derivatives interact with amino acid residues at the active site of Topo I and Topo II. The highest binding energy for the Topo I complex was shown by 1g and for the Topo II complex by 1e; these studies were validated by the analysis of decoys. Virtual mutations of Topo I and Topo II were tested, revealing the importance of certain active site residues on the binding mode and binding energy of the test triflamide derivatives. Overall, the results suggest that the compounds 1g and 1e could be drugs promising for the future design and development of anticancer agents.

Graphic abstract

Analysis of physicochemical, toxicological and pharmacokinetic properties of triflamide derivatives and their interactions with DNA topoisomerase I and II enzymes (Topo I and II) have been reported in this study. These computational results indicated that triflamide derivatives could present a dual inhibition by binding to the active site of both enzymes, validated by decoys analysis. On the other hand, the generation of virtual mutants of Topo I and II demonstrated the great influence of certain amino acids on the mode of union of triflamides.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Shewach D S and Kuchta R D 2009 Introduction to cancer chemotherapeutics Chem. Rev. 109 2859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Torre L A, Bray F, Siegel R L, Ferlay J, Lortet-Tieulent J and Jemal A 2015 Global Cancer Statistics 2012 CA: Cancer. J. Clin. 65 87

    Google Scholar 

  3. Ekwueme D U, Yabroff K R, Guy G P, Banegas M P, de Moor J S, Li C, Han X, Zheng Z, Soni A, Davidoff A, Rechis R and Virgo K S 2014 Medical costs and productivity losses of cancer survivors - United States, 2008-2011 Morb. Mortal. Wkly. Rep. 63 505

    Google Scholar 

  4. Badal S and Delgoda R (Eds.) 2016 Pharmacognosy: Fundamentals, Applications and Strategies (Oxford: Elsevier) p.738

  5. Reddy-Holdcraft S, Mehta P S and Agrawal A K 2014 Paclitaxel for relapsed or recurrent HIV-associated pediatric Kaposi’s sarcoma AIDS 28 800

    Article  PubMed  Google Scholar 

  6. Akazawa H 2017 Cardiotoxicity of Cancer Chemotherapy - Mechanisms and Therapeutic Approach Gan. To. Kagaku. Ryoho. 44 2058

    CAS  Google Scholar 

  7. Kelland L 2007 Broadening the clinical use of platinum drug-based chemotherapy with new analogues satraplatin and picoplatin Expert. Opin. Investig. Drugs. 16 1009

    Article  CAS  Google Scholar 

  8. Li F, Jiang T, Li Q and Ling X 2017 Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: Did we miss something in CPT analogue molecular targets for treating human disease such as cancer? Am. J. Cancer. Res. 7 2350

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Pommier Y 2006 Topoisomerase I inhibitors: Camptothecins and beyond Nat. Rev. Cancer. 6 789

    Article  CAS  PubMed  Google Scholar 

  10. Kollmannsberger C, Mross K, Jakob A, Kanz L and Bokemeyer C 1999 Topotecan - A novel topoisomerase I inhibitor: Pharmacology and clinical experience Oncology 56 1

    Article  CAS  PubMed  Google Scholar 

  11. Bracher F and Tremmel T 2017 From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story Arch. Pharm. (Weinheim). 350 8

  12. Mancini G, D’Annessa I, Coletta A, Sanna N, Chillemi G and Desideri A 2010 Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex PLoS One 5 10

    Article  CAS  Google Scholar 

  13. Chikamori K, Grozav A G, Kozuki T, Grabowski D, Ganapathi R and Ganapathi M K 2010 DNA topoisomerase II enzymes as molecular targets for cancer chemotherapy Curr. Cancer. Drug. Targets 10 758

    Article  CAS  Google Scholar 

  14. Fortune J M and Osheroff N 2000 Topoisomerase II as a target for anticancer drugs: when enzymes stop being nice Prog. Nucleic. Acid. Res. Mol. Biol. 64 221

    Article  CAS  Google Scholar 

  15. Li F, Ling X, Harris D, Liao J, Wang Y, Westover D, Jiang G, Xu B, Boland P M and Jin C 2017 Topoisomerase I (Top1): a major target of FL118 for its antitumor efficacy or mainly involved in its side effects of hematopoietic toxicity? Am. J. Cancer. Res. 7 370

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Beck W T, Danks M K 1991 Mechanisms of resistance to drugs that inhibit DNA topoisomerases Semin. Cancer. Biol. 2 235

    CAS  Google Scholar 

  17. Gómez-García O, Gómez E, Monzón-González C, Ramírez-Apan T and Álvarez-Toledano C 2017 An efficient strategy for the synthesis of 1-(trifluoromethylsulfonamido)-propan-2-yl esters and the evaluation of their cytotoxic activity Chem. Pharm. Bull. 65 248

    Article  Google Scholar 

  18. Scozzafava A, Owa T, Mastrolorenzo A and Supuran C T 2003 Anticancer and antiviral sulfonamides Curr. Med. Chem. 10 925

    CAS  Google Scholar 

  19. Casini A, Scozzafava A, Mastrolorenzo A and Supuran LT 2002 Sulfonamides and sulfonylated derivatives as anticancer agents Curr. Cancer. Drug. Targets. 2 55

    Article  CAS  Google Scholar 

  20. Cumaoglu A, Dayan S, Agkaya A, Ozkul Z and Ozpozan N K 2015 Synthesis and pro-apoptotic effects of new sulfonamidederivatives via activating p38/ERK phosphorylation in cancer cells J. Enzyme. Inhib. Med. Chem. 30 413

    Article  CAS  PubMed  Google Scholar 

  21. Shoaib Ahmad Shah S, Rivera G and Ashfaq M 2012 Recent Advances in Medicinal Chemistry of Sulfonamides. Rational Design as Anti-Tumoral, Anti-Bacterial and Anti-Inflammatory Agents Mini-Reviews. Med. Chem. 13 70

  22. Pommier Y, Leo E, Zhang H and Marchand C 2010 DNA topoisomerases and their poisoning by anticancer and antibacterial drugs Chem. Biol. 17 421

    CAS  Google Scholar 

  23. Delgado J L, Hsieh C M, Chan N L and Hiasa H 2018 Topoisomerases as anticancer targets Biochem. J. 475 373

    Article  CAS  PubMed  Google Scholar 

  24. Sander T, Freyss J, Von Korff M and Rufener C 2015 DataWarrior: An open-source program for chemistry aware data visualization and analysis J. Chem. Inf. Model. 55 460

    Article  CAS  PubMed  Google Scholar 

  25. Daina A, Michielin O and Zoete V 2017 SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules Sci. Rep. 3 42717

    Google Scholar 

  26. Furnham N, Laskowski R A and Thornton J M 2013 Abstracting knowledge from the Protein Data Bank Biopolymers 99 183

    Article  CAS  PubMed  Google Scholar 

  27. Phillips J C, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel R D, Kalé L and Schulten K 2005 Scalable molecular dynamics with NAMD J. Comput. Chem. 26 1781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Humphrey W, Dalke A and Schulten K 1996 VMD: visual molecular dynamics J. Mol. Graph. 14 33

    Article  CAS  PubMed  Google Scholar 

  29. Irwin J J and Shoichet B K 2005 ZINC–a free database of commercially available compounds for virtual screening J. Chem. Inf. Model. 45 177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pople J A, Head-Gordon M and Fox D J 1989 Gaussian-1 Theory: A General Procedure for Prediction of Molecular-Energies J. Chem. Phys. 90 5622

    Article  CAS  Google Scholar 

  31. Morris G M, Ruth H, Lindstrom W, Sanner M F, Belew R K, Goodsell D S and Olson A J 2009 Software news and updates AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility J. Comput. Chem. 30 2785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: Dassault Systèmes, 2016

    Google Scholar 

  33. Webb B and Sali A 2014 Comparative protein structure modeling using Modeller Curr. Protoc. Bioinformatics. 47 5.6.1

  34. Mysinger M M, Carchia M, Irwin J J and Shoichet B K 2012 Directory of Useful Decoys, Enhanced (DUD-E): Better Ligands and Decoys for Better Benchmarking J. Med. Chem. 55 6582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vraka C, Nics L, Wagner K H, Hacker M, Wadsak W and Mitterhauser M 2017 LogP, a yesterday’s value? Nucl. Med. Biol. 50 1

    Article  CAS  PubMed  Google Scholar 

  36. Trapani A, Lopedota A, Denora N, Laquintana V, Franco M, Latrofa A, Trapani G and Liso G 2005 A rapid screening tool for estimating the potential of 2-hydroxypropyl-beta-cyclodextrin complexation for solubilization purposes Int. J. Pharm. 295 163

    CAS  Google Scholar 

  37. Ertl P, Rohde B and Selzer P 2000 Fast Calculation of molecular polar surface area as a sum of fragment based contributions and its application to the prediction of drug transport properties J. Med. Chem. 43 3714

    Article  CAS  PubMed  Google Scholar 

  38. Hopkins A L, Groom C R and Alex A 2004 Ligand efficiency: A useful metric for lead selection Drug. Discov. Today 9 430

    Article  Google Scholar 

  39. Keserü G M and Makara G M 2009 The influence of lead discovery strategies on the properties of drug candidates Nat. Rev. Drug. Discov. 8 203

    Article  CAS  Google Scholar 

  40. Lipinski C A, Lombardo F, Dominy B W and Feeney P J 2001 Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1 Adv. Drug. Deliv. Rev. 46 3

    Article  CAS  Google Scholar 

  41. Champoux J J 2001 DNA topoisomerases: structure, function, and mechanism Annu. Rev. Biochem. 70 369

    Article  CAS  Google Scholar 

  42. Pan P, Li Y, Yu H, Sun H and Hou T 2013 Molecular principle of topotecan resistance by topoisomerase I mutations through molecular modeling approaches J. Chem. Inf. Model. 53 997

    Article  CAS  PubMed  Google Scholar 

  43. Tan H, Wang G, Li J, Meng G, Liu Z, Dong M, Li Y, Ju D and Zhang Q 2015 Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor Bioorg. Med. Chem. 23 118

    Article  CAS  PubMed  Google Scholar 

  44. Singh S, Das T, Awasthi M, Pandey V P, Pandey B and Dwivedi U N 2016 DNA topoisomerase-directed anticancerous alkaloids: ADMET-based screening, molecular docking, and dynamics simulation Biotechnol. Appl. Biochem. 63 125

    Article  CAS  Google Scholar 

  45. Xin L-T, Liu L, Shao C-L, Yu R L, Chen F L, Yue S J, Wang M, Guo Z L, Fan Y C, Guan H S and Wang C Y 2017 Discovery of DNA Topoisomerase I Inhibitors with Low-Cytotoxicity Based on Virtual Screening from Natural Products Mar. Drugs. 15 217

    Google Scholar 

  46. Scotti L, Mendonça F J B, Ribeiro F F, Tavares J F, da Silva M S, Barbosa Filho J M and Scotti M T 2018 Natural product inhibitors of topoisomerases: Review and docking study Curr. Protein. Pept. Sci. 19 275

    CAS  Google Scholar 

  47. Hande K R 1998 Etoposide: four decades of development of a topoisomerase II inhibitor Eur. J. Cancer. 34 1514

    CAS  Google Scholar 

  48. Wu C C, Li T K, Farh L, Lin L Y, Lin T S, Yu Y J, Yen T J, Chiang C W and Chan N L 2011 Structural Basis of Type II Topoisomerase Inhibition by the Anticancer Drug Etoposide Science 333 459

    Article  CAS  PubMed  Google Scholar 

  49. Kumar A and Bora U 2014 Molecular docking studies of curcumin natural derivatives with DNA topoisomerase I and II-DNA complexes Interdiscip. Sci. 6 285

    Article  CAS  PubMed  Google Scholar 

  50. Oksuzoglu E, Ertan-Bolelli T, Can H, Tarhan M, Ozturk K and Yildiz I 2017 Antitumor activities on HL-60 human leukemia cell line, molecular docking, and quantum-chemical calculations of some sulfonamide-benzoxazoles Artif. Cells. Nanomed. Biotechnol. 45 1388

    CAS  Google Scholar 

  51. Guianvarćh D, Duca M, Boukarim C, Kraus-Berthier L, Léonce S, Pierré A, Pfeiffer B, Renard P, Arimondo PB, Monneret C and Dauzonne D 2004 Synthesis and biological activity of sulfonamide derivatives of epipodophyllotoxin J. Med. Chem. 47 2365

    Article  CAS  Google Scholar 

  52. Ozawa Y, Kusano K, Owa T, Yokoi A, Asada M and Yoshimatsu K 2012 Therapeutic potential and molecular mechanism of a novel sulfonamide anticancer drug, indisulam (E7070) in combination with CPT-11 for cancer treatment Cancer. Chemother. Pharmacol. 69 1844

    Google Scholar 

  53. Lavanya R 2017 Sulphonamides: A Pharmaceutical Review Int. J. Pharma. Sci. 6 1

    Google Scholar 

  54. Shanti K D, Shanti M D and Meshram J S 2016 A convenient synthesis and molecular docking study of novel sulfonamides fused with Betti’s bases as DNA Topoisomerase II inhibitors J. Comput. Methods. Mol. Des. 6 13

    CAS  Google Scholar 

  55. Ajeet S R and Kumar A 2014 Designing of Sulfanilamide/Sulfacetamide Derivatives as Human Topoisomerase II Inhibitor: A Docking Approach Am. J. Pharmacol. Sci. 2 44

    Google Scholar 

  56. Graves A P, Brenk R and Shoichet B K 2005 Decoys for Docking J. Med. Chem. 48 3714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schmidtke P and Barril X 2010 Understanding and Predicting Druggability. A High-Throughput Method for Detection of Drug Binding Sites J. Med. Chem. 53 5858

  58. Sader S and Wu C 2017 Computational analysis of Amsacrine resistance in human topoisomerase II alpha mutants (R487K and E571K) using homology modeling, docking and all atom molecular dynamics simulation in explicit solvent J. Mol. Graph. Model. 72 209

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the Instituto Politécnico Nacional for two grants [SIP20181529 and SIP20172002] that gave financial support to the present research. We are grateful to Bruce Allan Larsen for proofreading the manuscript.

Author information

Authors and Affiliations

  1. Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N; Colonia Santo Tomás, 11340, Mexico City, Mexico

    ANDRADE-PAVÓN DULCE

  2. Departamento Química Orgánica, Escuela Nacional de Ciencias Biológicas-Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N; Colonia Santo Tomás, 11340, Mexico City, Mexico

    GÓMEZ-GARCÍA OMAR

  3. Instituto de Química-UNAM, Circuito Exterior, Ciudad Universitaria, C.P. 04510, Coyoacán, Mexico City, Mexico

    ÁLVAREZ-TOLEDANO CECILIO

Authors
  1. ANDRADE-PAVÓN DULCE
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. GÓMEZ-GARCÍA OMAR
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. ÁLVAREZ-TOLEDANO CECILIO
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to ANDRADE-PAVÓN DULCE or GÓMEZ-GARCÍA OMAR.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1950 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

DULCE, AP., OMAR, GG. & CECILIO, ÁT. Exploring the binding mode of triflamide derivatives at the active site of Topo I and Topo II enzymes: In silico analysis and precise molecular docking. J Chem Sci 132, 50 (2020). https://doi.org/10.1007/s12039-020-1750-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12039-020-1750-2

Keywords

Search

Navigation