Research Article
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Year 2020, Volume: 7 Issue: 2, 383 - 404, 23.06.2020
https://doi.org/10.18596/jotcsa.701243

Abstract

References

  • 1. Hirose Y, Ohkuma Y. Phosphorylation of the C-terminal domain of RNA polymerase II plays central roles in the integrated events of eucaryotic gene expression. Journal of Biochemistry. 2007;141(5):601–608.
  • 2.Shapiro GI, Harper JW. Anticancer drug targets: cell cycle and checkpoint control. Journal of Clinical Investigation. 1999 ;104 (12):1645–1653.
  • 3. Barriere C, Santamaria D, Cerqueira A, Galan J, Martin A et al. Mice thrivewithout Cdk4 and Cdk2. Molecular Oncology. 2007;1(1):72–83.
  • 4. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nature Reviews Cancer. 2009;9(3):153–166.
  • 5. Clark A. Natural products as a resource for new drugs. Pharmaceutical Research. 1996;13:1133–1144.
  • 6.Melik-Ogandzhanyan RG, Khachatryan VE, Gapoyan AS. Furo-, Thieno-, and Pyrrolo-[2,3- d]pyrimidines. Russian Chemical Reviews. 1985;54(3):262–276.
  • 7. Sanghvi YS, Larson SB, Matsumoto SS, Nord LD, Smee DF et al. Antitumor and antiviral activity of synthetic alpha and beta-ribonucleosides of certain substituted pyrimido[5,4-d]pyrimidines: a new synthetic strategy for exocyclic aminonucleosides. Journal of Medicinal Chemistry. 1989;32(3):629–637.
  • 8. Tenser RB, Gaydos A, Hay KA. Inhibition of herpes simplex virus reactivation by dipyridamole. Antimicrobial Agents and Chemotherapy. 2001;45 (12):3657–3659.
  • 9. de-la-Cruz JP, Carrasco T, Ortega G, Sanchez de-la-Cuesta F. Inhibition of ferrousinduced lipid peroxidation by pyrimido-pyrimidine derivatives in human liver membranes. Lipids. 1992; 27(3):192–194.
  • 10. Sharma P, Rane N, Gurram VK. Synthesis and QSAR studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents. Bioorganic & Medicinal Chemistry Letter. 2004;14(16):4185–4190.
  • 11. Ram VJ, Goel A, Sarkhel S, Maulik PR. A convenient synthesis and hepato protectiveactivity of imidazo[1,2- ]pyrimido[5,4- ]pyrimidine,tetraazaacenaphthene and tetraazaphenalene from cyclic ketene aminals through tandem addition-cyclization reactions. Bioorganic & Medicinal Chemistry. 2002;10(5):1275–1280.
  • 12. Huang WS, Liu S, Zou D, Thomas M, Wang Y. et al. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. Journal of Medicinal Chemistry. 2016;59(10):4948–4964.
  • 13. Corona SP, Generali D. Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2- advanced breast cancer. Drug Design, Development and Therapy. 2018;12:321–330.
  • 14. Krallinger M, Valencia A. Text-mining and information-retrieval services for molecular biology. Genome Biology. 2005;6(7):224.
  • 15. Marvinsketch 18.30.0, chemaxon, 2018.
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  • 17. Kakarala KK, Jamil K , Devaraji V. Structure and putative signaling mechanism of Protease activated receptor 2 (PAR2) - a promising target for breast cancer. Journal of Molecular Graphics and Modelling. 2014;53:179–199.
  • 18. Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR et al. Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules. Journal of Computer-Aided Molecular Design. 2007;21(12):681–691.
  • 19. Wang S, Griffiths G, Midgley CA, Barnett AL, Cooper M et al. Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents. Cell Chemical Biology. 2010;17(10):1111–1121.
  • 20. Jacobson MP, Pincus DL, Rapp CS, Day TJ, Honig B et al. A hierarchical approach to all-atom protein loop prediction. Proteins. 2004;55(2):351–367.
  • 21. Protein preparation, version 2.5, Schrodinger, LLC, New York, 2011.
  • 22. Sledz P, Caflisch A. Protein structure-based drug design: from docking to molecular dynamics. Current Opinion in Structural Biology. 2018;48:93–102.
  • 23. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry. 2004;47(7):1739–1749.
  • 24. Raha K, Merz KM. A quantum mechanics-based scoring function: study of zinc ion-mediated ligand binding. Journal of the American Chemical Society. 2004;126(4):1020–1021.
  • 25. Subhani S, Jayaraman A, Jamil K. Homology modelling and molecular docking of MDR1 with chemotherapeutic agents in non-small cell lung cancer. Biomedicine & Pharmacotherapy. 2015;71:37–45.
  • 26. Roy S, Kumar A, Baig MH, Masajik M, Provaznik I. Virtual screening, ADMET profiling, molecular docking and dynamics approaches to search for potent selective natural molecules based inhibitors against metallothionein-III to study Alzheimer’s disease. Methods. 2015; 83:105–110.
  • 27. Hou T, Wang J, Li Y, Wang W. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. Journal of Chemical Information and Modeling. 2011;51(1):69-82.
  • 28. Desmond, version 4.9, Schrodinger, LLC, New York, 2011.
  • 29. Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J. Interaction Models for Water in Relation to Protein Hydration pages 331–342. Springer Netherlands, Dordrecht. 1981.
  • 30. Hoover WG. Canonical dynamics: Equilibrium phase-space distributions. Physical Review A. 1985;31(3):1695–1697.
  • 31. Ma Z, Tuckerman M. Constant pressure ab initio molecular dynamics with discrete variable representation basis sets. The Journal of Chemical Physics. 2010;133(18):184110 . 32. Li J, Abel R, Zhu K , Cao Y, Zhao S, Friesner RA. The VSGB 2.0 model: a next generation energy model for high resolution protein structure modeling. Proteins. 2011;79 (10):2794–2812.

Identifying the Novel Pyrimidine-Based CDK2 Inhibitors as Anticancer Agents Using Text-Mining and Combined Molecular Modeling Approaches

Year 2020, Volume: 7 Issue: 2, 383 - 404, 23.06.2020
https://doi.org/10.18596/jotcsa.701243

Abstract

The cycline-dependent kinase (CDK) protein is an important target used in anti-cancer drug designing studies. Pyrimidine is a crucial fragment which is used in many FDA-approved drugs including anti-cancer drugs. In the current study, a small molecule database (Specs SC) that includes more than 210.000 compounds were used in text mining studies and 6668 molecules that carry “pyrimidine” fragments were filtered. These compounds were then screened at the binding pocket of CDK-2 target using molecular docking and molecular dynamics (MD) simulations approaches. Binding free energies of screened compounds were also compared with pyrimidine-based FDA approved anti-cancer drug Abemaciclib which targets CDK. Based on comparison of docking scores of screened compounds, top-7 hits were used in 100 ns MD simulations. Same MD simulations protocol (100 ns) were also applied to Abemaciclib-bound CDK-2 complex structure. Average Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) energies were then calculated. Our MM/GBSA results showed that 6 out of 7 compounds have better MM/GBSA scores than FDA approved compound Abemaciclib. Thus, together with combination of text mining and integrated molecular modeling approaches, we identified novel pyrimidine-based hits against CDK.

References

  • 1. Hirose Y, Ohkuma Y. Phosphorylation of the C-terminal domain of RNA polymerase II plays central roles in the integrated events of eucaryotic gene expression. Journal of Biochemistry. 2007;141(5):601–608.
  • 2.Shapiro GI, Harper JW. Anticancer drug targets: cell cycle and checkpoint control. Journal of Clinical Investigation. 1999 ;104 (12):1645–1653.
  • 3. Barriere C, Santamaria D, Cerqueira A, Galan J, Martin A et al. Mice thrivewithout Cdk4 and Cdk2. Molecular Oncology. 2007;1(1):72–83.
  • 4. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nature Reviews Cancer. 2009;9(3):153–166.
  • 5. Clark A. Natural products as a resource for new drugs. Pharmaceutical Research. 1996;13:1133–1144.
  • 6.Melik-Ogandzhanyan RG, Khachatryan VE, Gapoyan AS. Furo-, Thieno-, and Pyrrolo-[2,3- d]pyrimidines. Russian Chemical Reviews. 1985;54(3):262–276.
  • 7. Sanghvi YS, Larson SB, Matsumoto SS, Nord LD, Smee DF et al. Antitumor and antiviral activity of synthetic alpha and beta-ribonucleosides of certain substituted pyrimido[5,4-d]pyrimidines: a new synthetic strategy for exocyclic aminonucleosides. Journal of Medicinal Chemistry. 1989;32(3):629–637.
  • 8. Tenser RB, Gaydos A, Hay KA. Inhibition of herpes simplex virus reactivation by dipyridamole. Antimicrobial Agents and Chemotherapy. 2001;45 (12):3657–3659.
  • 9. de-la-Cruz JP, Carrasco T, Ortega G, Sanchez de-la-Cuesta F. Inhibition of ferrousinduced lipid peroxidation by pyrimido-pyrimidine derivatives in human liver membranes. Lipids. 1992; 27(3):192–194.
  • 10. Sharma P, Rane N, Gurram VK. Synthesis and QSAR studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents. Bioorganic & Medicinal Chemistry Letter. 2004;14(16):4185–4190.
  • 11. Ram VJ, Goel A, Sarkhel S, Maulik PR. A convenient synthesis and hepato protectiveactivity of imidazo[1,2- ]pyrimido[5,4- ]pyrimidine,tetraazaacenaphthene and tetraazaphenalene from cyclic ketene aminals through tandem addition-cyclization reactions. Bioorganic & Medicinal Chemistry. 2002;10(5):1275–1280.
  • 12. Huang WS, Liu S, Zou D, Thomas M, Wang Y. et al. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. Journal of Medicinal Chemistry. 2016;59(10):4948–4964.
  • 13. Corona SP, Generali D. Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2- advanced breast cancer. Drug Design, Development and Therapy. 2018;12:321–330.
  • 14. Krallinger M, Valencia A. Text-mining and information-retrieval services for molecular biology. Genome Biology. 2005;6(7):224.
  • 15. Marvinsketch 18.30.0, chemaxon, 2018.
  • 16. Banks JL, Beard HS, Cao Y, Cho AE, Damm W et al. Integrated Modeling Program, Applied Chemical Theory (IMPACT). Journal of Computational Chemistry. 2005;26(16):1752–1780.
  • 17. Kakarala KK, Jamil K , Devaraji V. Structure and putative signaling mechanism of Protease activated receptor 2 (PAR2) - a promising target for breast cancer. Journal of Molecular Graphics and Modelling. 2014;53:179–199.
  • 18. Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR et al. Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules. Journal of Computer-Aided Molecular Design. 2007;21(12):681–691.
  • 19. Wang S, Griffiths G, Midgley CA, Barnett AL, Cooper M et al. Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents. Cell Chemical Biology. 2010;17(10):1111–1121.
  • 20. Jacobson MP, Pincus DL, Rapp CS, Day TJ, Honig B et al. A hierarchical approach to all-atom protein loop prediction. Proteins. 2004;55(2):351–367.
  • 21. Protein preparation, version 2.5, Schrodinger, LLC, New York, 2011.
  • 22. Sledz P, Caflisch A. Protein structure-based drug design: from docking to molecular dynamics. Current Opinion in Structural Biology. 2018;48:93–102.
  • 23. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry. 2004;47(7):1739–1749.
  • 24. Raha K, Merz KM. A quantum mechanics-based scoring function: study of zinc ion-mediated ligand binding. Journal of the American Chemical Society. 2004;126(4):1020–1021.
  • 25. Subhani S, Jayaraman A, Jamil K. Homology modelling and molecular docking of MDR1 with chemotherapeutic agents in non-small cell lung cancer. Biomedicine & Pharmacotherapy. 2015;71:37–45.
  • 26. Roy S, Kumar A, Baig MH, Masajik M, Provaznik I. Virtual screening, ADMET profiling, molecular docking and dynamics approaches to search for potent selective natural molecules based inhibitors against metallothionein-III to study Alzheimer’s disease. Methods. 2015; 83:105–110.
  • 27. Hou T, Wang J, Li Y, Wang W. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. Journal of Chemical Information and Modeling. 2011;51(1):69-82.
  • 28. Desmond, version 4.9, Schrodinger, LLC, New York, 2011.
  • 29. Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J. Interaction Models for Water in Relation to Protein Hydration pages 331–342. Springer Netherlands, Dordrecht. 1981.
  • 30. Hoover WG. Canonical dynamics: Equilibrium phase-space distributions. Physical Review A. 1985;31(3):1695–1697.
  • 31. Ma Z, Tuckerman M. Constant pressure ab initio molecular dynamics with discrete variable representation basis sets. The Journal of Chemical Physics. 2010;133(18):184110 . 32. Li J, Abel R, Zhu K , Cao Y, Zhao S, Friesner RA. The VSGB 2.0 model: a next generation energy model for high resolution protein structure modeling. Proteins. 2011;79 (10):2794–2812.
There are 31 citations in total.

Details

Primary Language English
Subjects Biochemistry and Cell Biology (Other)
Journal Section Articles
Authors

Kader Sahin 0000-0002-9056-9000

Serdar Durdagı 0000-0002-0426-0905

Publication Date June 23, 2020
Submission Date March 9, 2020
Acceptance Date March 30, 2020
Published in Issue Year 2020 Volume: 7 Issue: 2

Cite

Vancouver Sahin K, Durdagı S. Identifying the Novel Pyrimidine-Based CDK2 Inhibitors as Anticancer Agents Using Text-Mining and Combined Molecular Modeling Approaches. JOTCSA. 2020;7(2):383-404.