Skip to main content

Pharmacophore development, drug-likeness analysis, molecular docking, and molecular dynamics simulations for identification of new CK2 inhibitors

Journal of Molecular Modeling volume 26, Article number: 160 (2020) Cite this article

Abstract

Protein kinase 2 (CK2), an essential serine/threonine casein kinase, is considered an interesting target for cancer treatments. Different molecular modeling approaches such as pharmacophore modeling, molecular docking, and molecular dynamics simulations have been used to develop new CK2 inhibitors. This study presents a pharmacophore model that was generated by combining and merging the structure-based and ligand-based pharmacophore features and validated using receiver operating characteristic (ROC). Based on validation results revealing good predictive ability, this pharmacophore model was used as a three-dimensional query in a virtual screening simulation. Several compounds with different chemical scaffolds were retrieved as hits, which were further analyzed and refined using several molecular property filters. The obtained compounds were then filtered and compared to the crystallographic ligand on the basis of their predicted docking energies, binding mode, and interactions with CK2 active site residues. This step resulted in a compound with a high pharmacophore fit value and better docking energy. Molecular dynamics simulation indicated stable binding of the predicted compound to CK2 protein, characterized by root mean square deviation (RMSD) and root mean square fluctuation (RMSF) and hydrogen bond.

Graphical abstract

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  1. Allende JE, Allende CC (1995). FASEB J 9(5):313–323

    CAS  Article  Google Scholar 

  2. Boldyreff B, Meggio F, Dobrowolska G, Pinna LA, Issinger OG (1993). Biochim Biophys Acta 1173(1):32–38. https://doi.org/10.1016/0167-4781(93)90239-A

    CAS  Article  PubMed  Google Scholar 

  3. Dobrowolska G, Lozeman FJ, Li D, Krebs EG (1999). Mol Cell Biochem 191(1–2):3–12. https://doi.org/10.1002/(SICI)1097-4644(199608)62:2<165::AID-JCB4>3.0.CO;2-Q

    CAS  Article  PubMed  Google Scholar 

  4. Guerra B, Siemer S, Boldyreff B, Issinger OG (1999). FEBS Lett 462(3):353–357. https://doi.org/10.1016/S0014-5793(99)01553-7

    CAS  Article  PubMed  Google Scholar 

  5. Pinna LA (1994). Cell Mol Biol Res 40(5–6):383–390

    CAS  PubMed  Google Scholar 

  6. Tawfic S, Faust RA, Gapany M, Ahmed K (1996). J Cell Biochem 62:165–171

    CAS  Article  Google Scholar 

  7. Faust M, Montenarh M (2000). Cell Tissue Res 301:329–340

    CAS  Article  Google Scholar 

  8. Filhol O, Martiel JL, Cochet C (2004). EMBO Rep 5:351–355. https://doi.org/10.1038/sj.embor.7400115

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Sonenshein GE (2002). Cancer Res 62(22):6770–6778 Published November 2002

    CAS  PubMed  Google Scholar 

  10. Yenice S, Davis AT, Goueli SA, Akdas A, Limas C, Ahmed K (1994). Prostate 24(1):11–16. https://doi.org/10.1002/pros.2990240105

    CAS  Article  PubMed  Google Scholar 

  11. Stalter G, Siemer S, Becht E, Ziegler M, Remberger K, Issinger OG (1994). Biochem Biophys Res Commun 202(1):141–147. https://doi.org/10.1006/bbrc.1994.1904

    CAS  Article  PubMed  Google Scholar 

  12. Scaglioni PP, Yung TM, Cai LF, Erdjument-Bromage H, Kaufman AJ, Singh B, Teruya-Feldstein J, Tempst P, Pandolfi PP (2006). Cell 126(2):269–283. https://doi.org/10.1016/j.cell.2006.05.041

    CAS  Article  PubMed  Google Scholar 

  13. Faust RA, Gapany M, Tristani P, Davis A, Adams GL, Ahmed K (1996). Cancer Lett 101(1):31–35

  14. Pinna LA (2002). J Cell Sci 115(20):3873–3878. https://doi.org/10.1242/jcs.00074

    CAS  Article  PubMed  Google Scholar 

  15. Litchfield DW (2003). Biochem J 369(1):1–15. https://doi.org/10.1042/BJ20021469

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Domańska K, Zieliński R, Kubiński K, Sajnaga E, Masłyk M, Bretner M, Szyszka R (2005). Acta Biochim Pol 52(4):947–951

    Article  Google Scholar 

  17. Kubiński K, Domańska K, Sajnaga E, Mazur E, Zieliński R, Szyszka R (2007). Mol Cell Biochem 295(1–2):229–236. https://doi.org/10.1007/s11010-006-9292-6

    CAS  Article  PubMed  Google Scholar 

  18. Cozza G, Pinna LA, Moro S (2012). Expert Opin Ther Pat 22(9):1081–1097. https://doi.org/10.1517/13543776.2012.717615

    CAS  Article  PubMed  Google Scholar 

  19. Raaf J, Brunstein E, Issinger OG, Niefind K (2008). Chem Biol 15(2):111–117. https://doi.org/10.1016/j.chembiol.2007.12.012

    CAS  Article  PubMed  Google Scholar 

  20. Pierre F, Chua PC, O'Brien SE, Siddiqui-Jain A, Bourbon P, Haddach M, Michaux J, Nagasawa J, Schwaebe MK, Stefan E, Vialettes A, Whitten JP, Chen TK, Darjania L, Stansfield R, Bliesath J, Drygin D, Ho C, Omori M, Proffitt C, Streiner N, Rice WG, Ryckman DM, Anderes K (2011). Mol Cell Biochem 356(1–2):37–43. https://doi.org/10.1007/s11010-011-0956-5

    CAS  Article  PubMed  Google Scholar 

  21. Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O'Brien SE, Bliesath J, Omori M, Huser N, Ho C, Proffitt C, Schwaebe MK, Ryckman DM, Rice WG, Anderes K (2010). Cancer Res 70(24):10288–10298. https://doi.org/10.1158/0008-5472.CAN-10-1893

    CAS  Article  PubMed  Google Scholar 

  22. Lolli G, Cozza G, Mazzorana M, Tibaldi E, Cesaro L, Donella-Deana A, Meggio F, Venerando A, Franchin C, Sarno S, Battistutta R, Pinna LA (2012). Biochemistry 51:6097–6107. https://doi.org/10.1021/bi300531c

    CAS  Article  PubMed  Google Scholar 

  23. McCarty MF (2015). Cancer Stud Mol Med Open J 2(1):39–51. https://doi.org/10.17140/CSMMOJ-2-105

    Article  Google Scholar 

  24. Bouaziz-Terrachet S, Toumi-Maouche A, Maouche B, Taïri-Kellou S (2010). J Mol Model 16(12):1919–1929. https://doi.org/10.1007/s00894-010-0679-7

    CAS  Article  PubMed  Google Scholar 

  25. Ounissi M, Kameli A, Tigrine C, Rachedi FZ (2018). Comput Biol Chem 77:1–16. https://doi.org/10.1016/j.compbiolchem.2018.07.005

    CAS  Article  PubMed  Google Scholar 

  26. Bouaziz-Terrachet S, Terrachet R, Tairi-Kellou S (2013). Med Chem Res 22(4):1529–1537. https://doi.org/10.1007/s00044-012-0174-z

    CAS  Article  Google Scholar 

  27. Khaldi-Khellafi N, Makhloufi-Chebli M, Oukacha-Hikem D, Terachet-Bouaziz S, Ould Lamara K, Idir T, Benazzouz-Touami A, Dumas F (2019). J Mol Struct 1181:261–269. https://doi.org/10.1016/j.molstruc.2018.12.104

    CAS  Article  Google Scholar 

  28. Belkhir-Talbi D, Makhloufi-Chebli M, Terrachet-Bouaziz S, Hikem Oukacha D, Ghemmit N, Ismaili L, Silva Artur MS, Hamdi M (2019). J Mol Struct 1179:495–505. https://doi.org/10.1016/j.molstruc.2018.11.035

  29. Lei B, Heng N, Dang X, Liu J, Yao X, Zhang C (2017). Mol BioSyst 13(7):1364–1369. https://doi.org/10.1039/c7mb00214a

    CAS  Article  PubMed  Google Scholar 

  30. Agnihotri P, Mishra AK, Mishra S, Sirohi VK, Sahasrabuddhe AA, Pratap JV (2017). J Chem Inf Model 57(4):815–825. https://doi.org/10.1021/acs.jcim.6b00642

    CAS  Article  PubMed  Google Scholar 

  31. Tewatia P, Malik BK, Sahi S (2012). Comb Chem High Throughput Screen 15(8):623–640. https://doi.org/10.2174/138620712802650559

    CAS  Article  PubMed  Google Scholar 

  32. Di-wu L, Li LL, Wang WJ, Xie HZ, Yang J, Zhang CH, Huang Q, Zhong L, Feng S, Yang SY (2012). J Mol Graph Model 36:42–47. https://doi.org/10.1016/j.jmgm.2012.03.004

    CAS  Article  PubMed  Google Scholar 

  33. Morshed MN, Muddassar M, Pasha FA, Cho SJ (2009). Chem Biol Drug Des 74(2):148–158. https://doi.org/10.1111/j.1747-0285.2009.00841.x

    CAS  Article  PubMed  Google Scholar 

  34. Sun HP, Zhu J, Chen FH, You QD (2011). Mol Inform 30(6–7):579–592. https://doi.org/10.1002/minf.201000178

    CAS  Article  PubMed  Google Scholar 

  35. Prudent R, Sautel CF, Cochet C (2010). Biochim Biophys Acta 1804(3):493–498. https://doi.org/10.1016/j.bbapap.2009.09.003

    CAS  Article  PubMed  Google Scholar 

  36. Yang SY (2010). Drug Discov Today 15(11–12):444–450. https://doi.org/10.1016/j.drudis.2010.03.013

    CAS  Article  PubMed  Google Scholar 

  37. Wolber G, Langer T (2005). J Chem Inf Model 45(1):160–169. https://doi.org/10.1021/ci049885e

    CAS  Article  PubMed  Google Scholar 

  38. FlexX version 2.3.2; BioSolveIT GmbH, Sankt Augustin, Germany, 2017, www.biosolveit.de/FlexX

  39. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kalé L, Schulten K (2005). J Comput Chem 26(16):1781–1802. https://doi.org/10.1002/jcc.20289

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Golub AG, Bdzhola VG, Ostrynska OV, Kyshenia IV, Sapelkin VM, Prykhod'ko AO, Kukharenko OP, Yarmoluk SM (2013). Bioorg Med Chem 21(21):6681–6689. https://doi.org/10.1016/j.bmc.2013.08.013

    CAS  Article  PubMed  Google Scholar 

  41. Irwin JJ, Sterling T, Mysinger MM, Bolstad ES, Coleman RG (2012). J Chem Inf Model 52(7):1757–1768. https://doi.org/10.1021/ci3001277 Epub 2012 Jun 15

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Marvin Sketch (version 18.28.0), calculation module developed by ChemAxon, http://www.chemaxon.com/products/marvin/marvinsketch/, 2014

  43. Cereto-Massagué A, Guasch L, Valls C, Mulero M, Pujadas G, Garcia-Vallvé S (2012). Bioinformatics 28(12):1661–1662. https://doi.org/10.1093/bioinformatics/bts249 Epub 2012 Apr 26

    CAS  Article  PubMed  Google Scholar 

  44. Truchon JF, Bayly CI (2007). J Chem Inf Model 47:488–508. https://doi.org/10.1021/ci600426e

    CAS  Article  PubMed  Google Scholar 

  45. Triballeau N, Acher F, Brabet I, Pin JP, Bertrand HO (2005). J Med Chem 48(7):2534–2547. https://doi.org/10.1021/jm049092j

    CAS  Article  PubMed  Google Scholar 

  46. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001). Adv Drug Deliv Rev 46(1–3):3–26. https://doi.org/10.1016/S0169-409X(00)00129-0

    CAS  Article  PubMed  Google Scholar 

  47. Verber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002). J Med Chem 45(12):2615–2623. https://doi.org/10.1021/jm020017n

    CAS  Article  Google Scholar 

  48. Ghose AK, Viswanadhan VN, Wendoloski JJ (1999). J Comb Chem 1(1):55–68

    CAS  Article  Google Scholar 

  49. Bickerton GR, Paolini GV, Besnard J, Muresan S, Hopkins AL (2012). Nat Chem 4(2):90–98. https://doi.org/10.1038/nchem.1243

  50. Baurin N, Baker R, Richardson C, Chen I, Foloppe N, Potter A, Jordan A, Roughley S, Parratt M, Greaney P, Morley D, Hubbard RE (2004). J Chem Inf Comput Sci 44(2):643–651

    CAS  Article  Google Scholar 

  51. Castello J, Ragnauth A, Friedman E, Rebholz H (2017). Pharmaceuticals (Basel) 10(1):E7. https://doi.org/10.3390/ph10010007

    CAS  Article  Google Scholar 

  52. Drwal MN, Banerjee P, Dunkel M, Wettig MR, Preissner R (2014). Nucleic Acids Res 42:W53–W58. https://doi.org/10.1093/nar/gku401

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Ibragimova GT, Wade RC (1998). Biophys J 74(6):2906–2911. https://doi.org/10.1021/ci034260m

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Essman U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995). J Chem Phys 103:8577–8593. https://doi.org/10.1063/1.470117

    Article  Google Scholar 

  55. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983). J Chem Phys 79:926–935. https://doi.org/10.1063/1.445869

    CAS  Article  Google Scholar 

  56. Humphrey W, Dalke A, Schulten K (1996). J Mol Graph 14:33–38 27–8

    CAS  Article  Google Scholar 

  57. Wallace AC, Laskowski RA, Thornton JM (1996). Protein Eng 8:127–134

    Article  Google Scholar 

  58. Protopopov MV, Starosyla SA, Borovykov OV, Sapelkin VN, Bilokin YV, Bdzhola VG, Yarmoluk SM (2017). Biopolymers and Cell 33(4):291–301. https://doi.org/10.7124/bc.00095B

    Article  Google Scholar 

  59. Haidar S, Bouaziz Z, Marminon C, Laitinen T, Poso A, Le Borgne, M, Jose J (2017). Pharmaceuticals (Basel) 10(1):8. https://doi.org/10.3390/ph10010008

  60. Pardhi T, Vasu K (2018). J Biomol Struct Dyn 36(1):177–194. https://doi.org/10.1080/07391102.2016.1270856

    CAS  Article  PubMed  Google Scholar 

  61. Shiri F, Pirhadi S, Rahmani A (2018). J Recept Signal Transduct Res 38(1):37–47. https://doi.org/10.1080/10799893.2017.1414844

    CAS  Article  PubMed  Google Scholar 

  62. Fei F, Zhou Z (2013). Expert Opin Ther Pat 23(9):1157–1179. https://doi.org/10.1517/13543776.2013.800857

    CAS  Article  PubMed  Google Scholar 

  63. Kinoshita T, Sekiguchi Y, Fukada H, Nakaniwa T, Tada T, Nakamura S, Kitaura K, Ohno H, Suzuki Y, Hirasawa A, Nakanishi I, Tsujimoto G (2011). Mol Cell Biochem 356(1–2):97–105. https://doi.org/10.1007/s11010-011-0960-9

    CAS  Article  PubMed  Google Scholar 

  64. Yde CW, Ermakova I, Issinger OG, Niefind K (2005). J Mol Biol 347(2):399–414. https://doi.org/10.1016/j.jmb.2005.01.003

    CAS  Article  PubMed  Google Scholar 

  65. Battistutta R, Negro A, Zanotti G (2000). Proteins 41(4):429–437

    CAS  Article  Google Scholar 

  66. Protopopov MV, Ostrynska OV, Starosyla SA, Vodolazhenko MA, Sirko SM, Gorobets NY, Bdzhola V, Desenko SM, Yarmoluk SM (2018). Mol Divers 22(4):991–998. https://doi.org/10.1007/s11030-018-9836-1

    CAS  Article  PubMed  Google Scholar 

  67. Liu H, Wang X, Wang J, Wang J, Li Y, Yang L, Li G (2011). Int J Mol Sci 12(10):7004–7021. https://doi.org/10.3390/ijms12107004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Chekanov MO, Ostrynska OV, Synyugin AR, Bdzhola VG, Yarmoluk SM (2014). J Enzyme Inhib Med Chem 29(3):338–343. https://doi.org/10.3109/14756366.2013.782024

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the Inte:Ligand Software-Entwicklungs- und Consulting GmbH, BioSolveIT team, and Professor Roman Laskowski for providing an academic free license for LigandScout 4.1.7, LeadIT 2.2.0, and LigPlot+ v.1.4.5 programs.

Author information

Affiliations

  1. Department of Chemistry, Faculty of Sciences, University of Mouloud Maamri, Tizi Ouzou, Algeria

    Sara Hammad, Rosa Meghnem & Dalila Meziane

  2. Laboratory of Theoretical Physico-Chemistry and Computer Chemistry, Faculty of Chemistry, University of Science and Technology Houari Boumédiène, Algiers, Algeria

    Sara Hammad, Souhila Bouaziz-Terrachet & Rosa Meghnem

  3. Department of Chemistry, Faculty of Sciences, University of Mohamed Bouguerra, Boumerdes, Algeria

    Souhila Bouaziz-Terrachet

Authors
  1. Sara Hammad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Souhila Bouaziz-Terrachet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosa Meghnem
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dalila Meziane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Souhila Bouaziz-Terrachet.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hammad, S., Bouaziz-Terrachet, S., Meghnem, R. et al. Pharmacophore development, drug-likeness analysis, molecular docking, and molecular dynamics simulations for identification of new CK2 inhibitors . J Mol Model 26, 160 (2020). https://doi.org/10.1007/s00894-020-04408-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-020-04408-2

Keywords

  • CK2
  • Virtual screening
  • FlexX
  • Structure-based pharmacophore modeling
  • Molecular dynamics
  • Ligand-based pharmacophore modeling and drug-likeness analysis