Skip to main content
SpringerLink
Log in

How can the cisplatin analogs with different amine act on DNA during cancer treatment theoretically?

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Cisplatin is a widely used anti-cancer drug which inhibits the replication and polymerization of DNA molecule while showing some side effects and drug resistance. For this reason, to enhance its therapeutic index, researchers have synthesized several thousand analogs and tested their properties. In this project, several cisplatin analogs were designed to theoretically study the biological activity and lipophilicity effects on amine changes. The amines of the cisplatin molecule were substituted with aliphatic amines in different analogs. Computational methods such as molecular dynamics simulation, molecular docking, and molecular mechanics Poisson-Boltzmann surface area analysis were performed to investigate the binding of six cisplatin derivatives with DNA. The binding affinity and potential interactions of these drugs with double-strand DNA were analyzed. The stability effect of these drugs was investigated via root-mean-square deviation and root-mean-square fluctuation analysis, which showed that some analogs can break base-pair interaction at the end of DNA and reduced the stability of DNA. Also, the results revealed that the hydrogen bond is one of the most important factors in the binding of cisplatin’s adduct to DNA. Molecular mechanics Poisson-Boltzmann surface area analysis indicated that electrostatic and van der Waals interactions are the most important deriving forces to the binding of cisplatin’s drug to DNA. Finally, data revealed that cisplatin and the cis-dichloro-dimethylamine-platin tendency for binding to DNA are greater than that of other analogs.

Graphical abstract

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

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The datasets generated during and analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Code availability

GROMACS software version 5.1.2.

Abbreviations

MMPBSA:

Molecular mechanics Poisson-Boltzmann surface area

MD simulation:

Molecular dynamics simulation

RMSD:

Root-mean-square deviation

RMSF:

Root-mean-square fluctuation

VdW:

Van der Waals

DNA:

Deoxyribonucleic acid

cis-[Pt(methyl-NH2)2Cl2]:

cis-Dichloro-dimethylamine-platin (II)

cis-[Pt(propyl-NH2)2Cl2]:

cis-Dichloro-dipropylamine-platin (II)

cis-[Pt(butyl-NH2)2Cl2]:

cis-Dichloro-dibutylamine-platin (II)

cis-[Pt(isobutyl-NH2)2Cl2]:

cis-Dichloro-diisobutylamine-platin (II)

cis-[Pt(tertbutyl-NH2)2Cl2]:

cis-Dichloro-ditertbutylamine-platin (II)

cis-[Pt(isopentyl-NH2)2Cl2]:

cis-Dichloro-diisopentylamine-platin (II

References

  1. Hambley TW (2001) Platinum binding to DNA: structural controls and consequences. J Chem Soc Dalton Trans 19:2711–2718

    Google Scholar 

  2. Eriksson M, Hassan S, Larsson R, Linder S, Ramqvist T, Lövborg H, Vikinge T, Figgemeier E, Müller J, Stetefeld J, Dalianis T, Ozbek S (2009) Utilization of a right-handed coiled-coil protein from archaebacterium staphylothermus marinus as a carrier for cisplatin. Anticancer Res 29:11–18

  3. Reedijk J (2003) New clues for platinum antitumor chemistry: kinetically controlled metal binding to DNA. Proc Natl Acad Sci 100(7):3611–3616

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Michalke B (2010) Platinum speciation used for elucidating activation or inhibition of Pt-containing anti-cancer drugs. J Trace Elem Med Biol 24(2):69–77

    CAS  PubMed  Google Scholar 

  5. Trimmer EE, Essigmann JM (1999) Cisplatin. Essays Biochem 34:191–211

    CAS  PubMed  Google Scholar 

  6. Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7(8):573–584

    CAS  PubMed  Google Scholar 

  7. Jamieson ER, Lippard SJ (1999) Structure, recognition, and processing of cisplatin− DNA adducts. Chem Rev 99(9):2467–2498

    CAS  PubMed  Google Scholar 

  8. Chen B, Zhou L (2015) Computational study on mechanisms of the anticancer drug: cisplatin and novel polynuclear platinum (II) interaction with sulfur-donor biomolecules and DNA purine bases. Comput Theor Chem 1074:36–49

    CAS  Google Scholar 

  9. Yang D et al (1995) Structure and isomerization of an intrastrand cisplatin-cross-linked octamer DNA duplex by NMR analysis. Biochemistry 34(39):12912–12920

    CAS  PubMed  Google Scholar 

  10. Ciccarelli RB et al (1985) In vivo effects of cis-and trans-diamminedichloroplatinum (II) on SV40 chromosomes: differential repair, DNA-protein crosslinking, and inhibition of replication. Biochemistry 24(26):7533–7540

    CAS  PubMed  Google Scholar 

  11. Jordan P, Carmo-Fonseca M (2000) Molecular mechanisms involved in cisplatin cytotoxicity. Cell Mol Life Sci 57(8–9):1229–1235

    CAS  PubMed  Google Scholar 

  12. Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22(47):7265–7279

    CAS  PubMed  Google Scholar 

  13. Sherman SE et al (1988) Crystal and molecular structure of cis-[Pt (NH3) 2 [d (pGpG)]], the principal adduct formed by cis-diamminedichloroplatinum (II) with DNA. J Am Chem Soc 110(22):7368–7381

    CAS  Google Scholar 

  14. Malinge J-M, Schwartz A, Leng M (1987) Characterization of the ternary complexes formed in the reaction of cis-diamminedichloro platinum (II), ethidium bromide, and nucleic acids. Nucleic Acids Res 15(4):1779–1797

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Eastman A (1990) Activation of programmed cell death by anticancer agents: cisplatin as a model system. Cancer Cell 2(8–9):275–280

    CAS  Google Scholar 

  16. Fichtinger-Schepman AMJ et al (1985) Adducts of the antitumor drug cis-diamminedichloroplatinum (II) with DNA: formation, identification, and quantitation. Biochemistry 24(3):707–713

    CAS  PubMed  Google Scholar 

  17. Inagaki K, Kidani Y (1983) Studies on the reaction products of guanylyl (3′-5′) adenosine with cis-Pt (NH2)2Cl2and [Pt(NH3)3Cl]Cl. Inorganica Chim Acta 80:171–176

    CAS  Google Scholar 

  18. Van Hemelryck B et al (1987) Sequence-dependent platinum chelation by adenylyl (3′-5′) guanosine and guanylyl (3′-5′) adenosine reacting with cis-diamminedichloroplatinum (II) and its diaqua derivative. Inorg Chem 26(6):787–795

    Google Scholar 

  19. Mantri Y, Lippard SJ, Baik M-H (2007) Bifunctional binding of cisplatin to DNA: why does cisplatin form 1, 2-intrastrand cross-links with AG but not with GA? J Am Chem Soc 129(16):5023–5030

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kelland LR (2000) Preclinical perspectives on platinum resistance. Drugs 59(4):1–8

    CAS  PubMed  Google Scholar 

  21. Wilson JJ, Lippard SJ (2014) Synthetic methods for the preparation of platinum anticancer complexes. Chem Rev 114(8):4470–4495

    CAS  PubMed  Google Scholar 

  22. Johnstone TC, Suntharalingam K, Lippard SJ (2016) The next generation of platinum drugs: targeted Pt (II) agents, nanoparticle delivery, and Pt (IV) prodrugs. Chem Rev 116(5):3436–3486

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Weiss RB, Christian MC (1993) New cisplatin analogues in development. Drugs 46(3):360–377

    CAS  PubMed  Google Scholar 

  24. Shah N, Dizon DS (2009) New-generation platinum agents for solid tumors. Future Oncol 5(1):33–42

    CAS  PubMed  Google Scholar 

  25. Wang D, Lippard SJ (2005) Cellular processing of platinum anticancer drugs. Nat Rev Drug Disc 4(4):307–320

    CAS  Google Scholar 

  26. Kelland LR (1993) New platinum antitumor complexes. Crit Rev Oncol Hematol 15(3):91–219

    Google Scholar 

  27. Rixe O et al (1996) Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute’s Anticancer Drug Screen panel. Biochem Pharmacol 52(12):1855–1865

    CAS  PubMed  Google Scholar 

  28. Alberto ME, Butera V, Russo N (2011) Which one among the Pt-containing anticancer drugs more easily forms monoadducts with G and A DNA bases? A comparative study among oxaliplatin, nedaplatin, and carboplatin. Inorg Chem 50(15):6965–6971

    CAS  PubMed  Google Scholar 

  29. Natarajan G, Malathi R, Holler E (1999) Increased DNA-binding activity of cis-1, 1-cyclobutanedicarboxylatodiammineplatinum (II)(carboplatin) in the presence of nucleophiles and human breast cancer MCF-7 cell cytoplasmic extracts: activation theory revisited. Biochem Pharmacol 58(10):1625–1629

    CAS  PubMed  Google Scholar 

  30. Raymond E, Faivre S, Woynarowski JM, Chaney SG (1998) Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol 25(2 Suppl 5):4–12

  31. Wiseman LR et al (1999) Oxaliplatin. Drugs Aging 14(6):459–475

    CAS  PubMed  Google Scholar 

  32. Alcindor T, Beauger N (2011) Oxaliplatin: a review in the era of molecularly targeted therapy. Current Oncol (Toronto, Ont.) 18(1):18–25

    CAS  Google Scholar 

  33. Wu Y et al (2007) Solution structures of a DNA dodecamer duplex with and without a cisplatin 1, 2-d (GG) intrastrand cross-link: comparison with the same DNA duplex containing an oxaliplatin 1, 2-d (GG) intrastrand cross-link. Biochemistry 46(22):6477–6487

    CAS  PubMed  Google Scholar 

  34. Spiegel K, Rothlisberger U, Carloni P (2004) Cisplatin binding to DNA oligomers from hybrid Car-Parrinello/molecular dynamics simulations. J Phys Chem B 108(8):2699–2707

    CAS  Google Scholar 

  35. Scheeff ED, Briggs JM, Howell SB (1999) Molecular modeling of the intrastrand guanine-guanine DNA adducts produced by cisplatin and oxaliplatin. Mol Pharmacol 56(3):633–643

    CAS  PubMed  Google Scholar 

  36. Magistrato A et al (2006) Binding of novel azole-bridged dinuclear platinum (II) anticancer drugs to DNA: insights from hybrid QM/MM molecular dynamics simulations. J Phys Chem B 110(8):3604–3613

    CAS  PubMed  Google Scholar 

  37. Elizondo-Riojas M-A, Kozelka J (2001) Unrestrained 5 ns molecular dynamics simulation of a cisplatin-DNA 1, 2-GG adduct provides a rationale for the NMR features and reveals increased conformational flexibility at the platinum binding site. J Mol Biol 314(5):1227–1243

    CAS  PubMed  Google Scholar 

  38. Olusanya TO et al (2018) Liposomal drug delivery systems and anticancer drugs. Molecules 23(4):907

    PubMed Central  Google Scholar 

  39. Liu D et al (2013) Application of liposomal technologies for delivery of platinum analogs in oncology. Int J Nanomed 8:3309

    Google Scholar 

  40. Zalba S, Garrido MJ (2013) Liposomes, a promising strategy for clinical application of platinum derivatives. Expert Opin Drug Deliv 10(6):829–844

    CAS  PubMed  Google Scholar 

  41. Ghosh S (2019) Cisplatin: the first metal based anticancer drug. Bioorg Chem 88:102925. https://doi.org/10.1016/j.bioorg.2019.102925

    Article  CAS  PubMed  Google Scholar 

  42. Yassin AM, Elnouby M, El-Deeb NM, Hafez EE (2016) Tungsten oxide nanoplates; the novelty in targeting metalloproteinase-7 gene in both cervix and colon cancer cells. Appl Biochem Biotechnol 180(4):623–637. https://doi.org/10.1007/s12010-016-2120-x

    Article  CAS  PubMed  Google Scholar 

  43. 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 176(7):1996–2017. https://doi.org/10.1007/s12010-015-1696-x

    Article  CAS  PubMed  Google Scholar 

  44. Hardie ME, Kava HW, Murray V (2016) Cisplatin analogues with an increased interaction with DNA: prospects for therapy. Curr Pharm Des 22(44):6645–6664

    CAS  PubMed  Google Scholar 

  45. Frisch M et al (2016) Gaussian 16 Rev. B. 01, Wallingford, CT

  46. Berman HM et al (2002) The protein data bank. Acta Crystallogr D Biol Crystallogr 58(6):899–907

    PubMed  Google Scholar 

  47. Morris GM et al (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19(14):1639–1662

    CAS  Google Scholar 

  48. Huey R et al (2007) A semiempirical free energy force field with charge-based desolvation. J Comput Chem 28(6):1145–1152

    CAS  PubMed  Google Scholar 

  49. DeLano WL (2002) PyMOL: an open-source molecular graphics tool, CCP4 newsletter pro. Crystallogr 40(1):82–92

  50. Pettersen EF et al (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25(13):1605–1612

    CAS  PubMed  Google Scholar 

  51. Hess B et al (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4(3):435–447

    CAS  PubMed  Google Scholar 

  52. Wang J et al (2004) Development and testing of a general amber force field. J Comput Chem 25(9):1157–1174

    CAS  PubMed  Google Scholar 

  53. Lindorff-Larsen K et al (2010) Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins Struct Funct Bioinf 78(8):1950–1958

    CAS  Google Scholar 

  54. Yesylevskyy S et al (2015) Empirical force field for cisplatin based on quantum dynamics data: case study of new parameterization scheme for coordination compounds. J Mol Model 21(10):268

    CAS  PubMed  Google Scholar 

  55. Lopes JF et al (2006) Monte Carlo simulation of cisplatin molecule in aqueous solution. J Phys Chem B 110(24):12047–12054

    CAS  PubMed  Google Scholar 

  56. Paschoal D et al (2012) The role of the basis set and the level of quantum mechanical theory in the prediction of the structure and reactivity of cisplatin. J Comput Chem 33(29):2292–2302

    CAS  PubMed  Google Scholar 

  57. Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126:014101

    PubMed  Google Scholar 

  58. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N⋅ log (N) method for Ewald sums in large systems. J Chem Phys 98(12):10089–10092

    CAS  Google Scholar 

  59. Andersen HC (1983) Rattle: a “velocity” version of the shake algorithm for molecular dynamics calculations. J Comput Phys 52(1):24–34

    CAS  Google Scholar 

  60. Miyamoto S, Kollman PA (1992) Settle: an analytical version of the SHAKE and RATTLE algorithm for rigid water models. J Comput Chem 13(8):952–962

    CAS  Google Scholar 

  61. Kumari R et al (2014) gmmpbsa: a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 54(7):1951–1962

    CAS  PubMed  Google Scholar 

Download references

Funding

Chemistry & Chemical Engineering Research Center of Iran financially supported this project.

Author information

Authors and Affiliations

  1. Chemistry & Chemical Engineering Research Center of Iran, Tehran, Iran

    Arezo Rahiminezhad, Mahboube Eslami Moghadam & A. Wahid Mesbah

  2. Department of Cell & Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran

    Adeleh Divsalar

Authors
  1. Arezo Rahiminezhad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahboube Eslami Moghadam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adeleh Divsalar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Wahid Mesbah
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors confirm contribution to the paper as follows: study conception and design: Mahboube Eslami Moghadam; data collection, analysis, and interpretation of results: Arezo Rahiminezhad and Mahboube Eslami Moghadam; draft manuscript preparation: Arezo Rahiminezhad, Mahboube Eslami Moghadam, Adeleh Divsalar, and A. Vahid Mesbah. All authors reviewed the results and approved the final version of the manuscript.

Corresponding author

Correspondence to Mahboube Eslami Moghadam.

Ethics declarations

Ethics approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 3840 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rahiminezhad, A., Moghadam, M.E., Divsalar, A. et al. How can the cisplatin analogs with different amine act on DNA during cancer treatment theoretically?. J Mol Model 28, 2 (2022). https://doi.org/10.1007/s00894-021-04984-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-021-04984-x

Keywords

Search

Navigation