Advertisement

Portraying the selectivity of GSK-3 inhibitors towards CDK-2 by 3D similarity and molecular docking

  • Liliana Pacureanu
  • Sorin Avram
  • Alina Bora
  • Ludovic Kurunczi
  • Luminita CrisanEmail author
Original Research
  • 26 Downloads

Abstract

The striking structural resemblance between adenosine triphosphate (ATP) binding sites of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinase-2 (CDK-2) raises numerous off-target selectivity problems in lead-identification processes that may jeopardize their progress into safe and effective drugs. The structural disparities between GSK-3 and CDK-2 in terms of inhibitors chemical space and binding site characteristics were investigated computationally by ligand-based (3D-similarity search) and structure-based (molecular docking) methods to reproduce the selectivity trend of indirubin derivatives. We attempted to assess distinctive key selectivity features of GSK-3 over CDK-2 with focus on indirubins and to provide a cascade virtual screening approach capable to identify suitable de novo GSK-3 selective scaffolds. Seven inhibitors with higher predicted interaction energies against GSK-3 compared to the highly active reference inhibitor were proposed. Concerted effects between 3D similarity search and docking afforded an exhaustive characterization of the binding site interactions. In spite of inherent challenges and limitations, the workflow developed hereby can be applied to other GSK-3 inhibitors, which display similar inhibitory profile against CDK-2, to rationally design potentially selective scaffolds.

Keywords

Glycogen synthase kinase-3 Cyclin-dependent kinase-2 Indirubin Similarity search Docking Selectivity 

Abbreviations

GSK-3

Glycogen synthase kinase-3

CDK-2

Cyclin-dependent kinases-2

MAPK

Mitogen-activated protein kinase

CLK

CDC-like kinase

ATP

Adenosine triphosphate

CDK-2 WII

CDK-2 weak inhibitors and inactive dataset

CDK-2 decoys

DUD-E CDK-2 decoys dataset

IXM

Indirubin-3′-monoxime; (Z)-1H,1’H-[2,3′]bisindolylidene-3,2′-dione-3-oxime

INR

Indirubin-5-sulphonic acid; (2Z)-2′,3-dioxo-1,1′,2′,3-tetrahydro-2,3′-bisindole-5′-sulfonic acid

TC

Tanimoto combo

ST

Shape Tanimoto

SC

Scaled color

CS

Combo score

CG4

Chemgauss4

Notes

Acknowledgments

We thank OpenEye Scientific Software, Chemaxon, for providing us an academic license, to Dr. Ramona Curpan, Institute of Chemistry Timisoara, for providing access to Schrodinger software acquired through the project PN–II–RU PD_502 funded by UEFISCDI–CNCSIS Romania, to BIOVIA Discovery Studio for the free license and SureChem for the free trial license.

Funding information

This project was financially supported by the Institute of Chemistry Timisoara of the Romanian Academy, Project 1.2.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Supplementary material

11224_2018_1224_MOESM1_ESM.pdf (892 kb)
ESM 1 (PDF 891 kb)

References

  1. 1.
    Woodgett JR (1990). EMBO J 9:2431–2438PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Lee HC, Tsai JN, Liao PY, Tsai WY, Lin KY, Chuang CC, Sun CK, Chang WC, Tsai HJ (2007). BMC Dev Biol 7:93PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Nikoulina SE, Ciaraldi TP, Mudaliar S, Carter L, Johnson K, Henry RR (2002). Diabetes 51:2190–2198PubMedCrossRefGoogle Scholar
  4. 4.
    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995). Nature 378:785–789PubMedCrossRefGoogle Scholar
  5. 5.
    Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P (1998). Curr Biol 8:573–581PubMedCrossRefGoogle Scholar
  6. 6.
    Ougolkov AV, Billadeau DD (2006). Future Oncol 2:91–100PubMedCrossRefGoogle Scholar
  7. 7.
    Soos TJ, Meijer L, Nelson PJ (2006). Drug News Perspect 19:325–328PubMedCrossRefGoogle Scholar
  8. 8.
    Ko HW, Kim EY, Chiu J, Vanselow JT, Kramer A, Edery I (2010). J Neurosci 30:12664–12675PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM, Eisenbrand G, Meijer L (2001). J Biol Chem 276:251–260PubMedCrossRefGoogle Scholar
  10. 10.
    Bhat R, Xue Y, Berg S, Hellberg S, Ormö M, Nilsson Y, Radesäter A-C, Jerning E, Markgren P-O, Borgegård T, Nylöf M, Giménez-Cassina A, Hernández F, Lucas JJ, Díaz-Nido J, Avila J (2003). J Biol Chem 278:45937–45945PubMedCrossRefGoogle Scholar
  11. 11.
    Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A (2009). J Pharmacol 156:885–898Google Scholar
  12. 12.
    Coghlan MP, Culbert AA, Cross DAE, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L, Mills D, Brown MJ, Haigh D, Ward RW, Smith DG, Murray KJ, Reith AD, Holder JC (2000). Chem Biol 7:793–803PubMedCrossRefGoogle Scholar
  13. 13.
    Serenó L, Coma M, Rodríguez M, Sánchez-Ferrer P, Sánchez MB, Gich I, Agulló JM, Pérez M, Avila J, Guardia-Laguarta C, Clarimón J, Lleó A, Gómez-Isla T (2009). Neurobiol Dis 35:359–367PubMedCrossRefGoogle Scholar
  14. 14.
    Takashima A (2009). J Pharmacol Sci 109:174–178PubMedCrossRefGoogle Scholar
  15. 15.
    Mazanetz MP, Fischer PM (2007). Nat Rev Drug Discov 6:464–479PubMedCrossRefGoogle Scholar
  16. 16.
    Spittaels K, van den Haute C, van Dorpe J, Geerts H, Mercken M, Bruynseels K, Lasrado R, Vandezande K, Laenen I, Boon T, van Lint J, Vandenheede J, Moechars D, Loos R, van Leuven F (2000). J Biol Chem 275:41340–41349PubMedCrossRefGoogle Scholar
  17. 17.
    Caballero J, Zilocchi S, Tiznado W, Collina S, Rossi D (2011). Chem Biol Drug Des 78:631–641PubMedCrossRefGoogle Scholar
  18. 18.
    Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, Flocco M (2003). J Mol Biol 333:393–407PubMedCrossRefGoogle Scholar
  19. 19.
    Berg S, Bergh M, Hellberg S, Hogdin K, Lo-Alfredsson Y, Soderman P, Von Berg S, Weigelt T, Ormo M, Xue Y, Tucker J, Neelissen J, Jerning E, Nilsson Y, Bhat R (2012). J Med Chem 55:9107–9119PubMedCrossRefGoogle Scholar
  20. 20.
    Georgievska B, Sandin J, Doherty J, Mörtberg A, Neelissen J, Andersson A, Gruber S, Nilsson Y, Schött P, Arvidsson PI, Hellberg S, Osswald G, Berg S, Fälting J, Bhat RV (2013). J Neurochem 125:446–456PubMedCrossRefGoogle Scholar
  21. 21.
    Pradeep H, Rajanikant GK (2012). Mol Divers 16:553–562PubMedCrossRefGoogle Scholar
  22. 22.
    Quesada-Romero L, Mena-Ulecia K, Tiznado W, Caballero J (2014). PLoS One 9:e102212PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Meijer L, Greengard P, Knockaert M, Skaltsounis A (2007) Patent US 2007/0276025 A1Google Scholar
  24. 24.
    Polychronopoulos P, Magiatis P, Skaltsounis AL, Myrianthopoulos V, Mikros E, Tarricone A, Musacchio A, Roe SM, Pearl L, Leost M, Greengard P, Meijer L (2004). J Med Chem 47:935–946PubMedCrossRefGoogle Scholar
  25. 25.
    Vougogiannopoulou K, Skaltsounis AL (2012). Planta Med 78:1515–1528PubMedCrossRefGoogle Scholar
  26. 26.
    Vougogiannopoulou K, Ferandin Y, Bettayeb K, Myrianthopoulos V, Lozach O, Fan Y, Johnson CH, Magiatis P, Skaltsounis A-L, Mikros E, Meijer L (2008). J Med Chem 51:6421–6431PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Choi S-J, Lee J-E, Jeong S-Y, Im I, Lee S-D, Lee E-L, Lee SK, Kwon SM, Ahn S-G, Yoon J-H, Han S-Y, Kim J-I, Kim Y-C (2010). J Med Chem 53:3696–3706PubMedCrossRefGoogle Scholar
  28. 28.
    Suzuki K, Adachi R, Hirayama A, Watanabe H, Otani S, Watanabe Y, Kasahara T (2005). Br J Haematol 130:681–690PubMedCrossRefGoogle Scholar
  29. 29.
    Ferandin Y, Bettayeb K, Kritsanida M, Lozach O, Polychronopoulos P, Magiatis P, Skaltsounis AL, Meijer L (2006). J Med Chem 49:4638–4649PubMedCrossRefGoogle Scholar
  30. 30.
    Hoessel R, Leclerc S, Endicott JA, Nobel ME, Lawrie A, Tunnah P, Leost M, Damiens E, Marie D, Marko D, Niederberger E, Tang W, Eisenbrand G, Meijer L (1999) Nature. Cell Biol 1:60–67Google Scholar
  31. 31.
    Davies TG, Tunnah P, Meijer L, Marko D, Eisenbrand G, Endicott JA, Noble ME (2001). Structure 9:389–397PubMedCrossRefGoogle Scholar
  32. 32.
    RCSB Protein Data Bank, RCSB PDB, https://www.rcsb.org/structure/1Q41 (accessed on January 2018)
  33. 33.
    RCSB Protein Data Bank, RCSB PDB, https://www.rcsb.org/structure/1E9H (accessed on January 2018)
  34. 34.
    Crisan L, Avram S, Pacureanu L (2017). Mol Divers 21:385–405PubMedCrossRefGoogle Scholar
  35. 35.
    Aouidate A, Ghaleb A, Ghamali M, Chtita S, Ousaa A, M’b C, Sbai A, Bouachrine M, Lakhlifi T (2018). Struct Chem.  https://doi.org/10.1007/s11224-018-1134-0 CrossRefGoogle Scholar
  36. 36.
    Crisan L, Pacureanu L, Bora A, Avram S, Kurunczi L, Simon Z (2013). Cent Eur J Chem 1:63–77CrossRefGoogle Scholar
  37. 37.
    Katritzky AR, Pacureanu LM, Dobchev DA, Fara DC, Duchowicz PR, Karelson M (2006). Bioorg Med Chem 14:4987–5002PubMedCrossRefGoogle Scholar
  38. 38.
    Pacureanu L, Crisan L, Bora A, Avram S, Kurunczi L (2012). Monatsh Chem 143:1559–1573CrossRefGoogle Scholar
  39. 39.
    Crisan L, Pacureanu L, Bora A, Avram S, Kurunczi L (2013). Cent Eur J Chem 11:1644–1656CrossRefGoogle Scholar
  40. 40.
    Crisan L, Pacureanu L, Avram S, Bora A, Avram S, Kurunczi L (2014) J Enz Inhib. Med Chem 29:599–610Google Scholar
  41. 41.
    Quesada-Romero L, Caballero J (2014). Mol Divers 18:149–159PubMedCrossRefGoogle Scholar
  42. 42.
    Li X, Wang X, Tian Z, Zhao H, Liang D, Li W, Qiu Y, Lu S (2014). J Mol Model 20:2407PubMedCrossRefGoogle Scholar
  43. 43.
    Kirchmair J, Distinto S, Schuster D, Spitzer G, Langer T, Wolber G (2008). Curr Med Chem 15:2040–2053PubMedCrossRefGoogle Scholar
  44. 44.
    Kim S, Bolton EE, Bryant SH (2011). J Cheminform 3:26PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Grant JA, Gallardo MA, Pickup B (1996). J Comp Chem 17:1653–1666CrossRefGoogle Scholar
  46. 46.
    Gaulton A, Hersey A, Nowotka M, Bento AP, Chambers J, Mendez D, Mutowo P, Atkinson F, Bellis LJ, Cibrián-Uhalte E, Davies M, Dedman N, Karlsson A, Magariños MP, Overington JP, Papadatos G, Smit I, Leach AR (2017) The ChEMBL database in 2017. Nucleic Acids Res. 45(D1):D945–D954PubMedCrossRefGoogle Scholar
  47. 47.
    Mysinger MM, Carchia M, Irwin JJ, Shoichet BK (2012). J Med Chem 55:6582–6594PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Dean PM (1990) In: Maggiora GM, Johnson MA (eds) Concepts and applications of molecular similarity. Wiley&Sons, New YorkGoogle Scholar
  49. 49.
    Akabli T, Toufik H, Yasri A, Bih H, Lamchouri F (2018). Struct Chem.  https://doi.org/10.1007/s11224-018-1141-1 CrossRefGoogle Scholar
  50. 50.
    OMEGA v.2.5.1.4 OpenEye Scientific Software Inc. Santa Fe NM, USA www.eyesopen.com
  51. 51.
    Hawkins PCD, Skillman AG, Warren GL, Ellingson BA, Stahl MT (2010). J Chem Inf Model 50:572–584PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Hawkins PCD, Nicholls A (2012). J Chem Inf Model 52:2919–2936PubMedCrossRefGoogle Scholar
  53. 53.
    Boström J, Greenwood JR, Gottfries J (2003). J Mol Graph Model 21:449–462PubMedCrossRefGoogle Scholar
  54. 54.
    ROCS v.3.2.1.4 OpenEye Scientific Software Inc. Santa Fe NM, USA www.eyesopen.com
  55. 55.
    Hawkins PCD, Skillman AG, Nicholls A (2007). J Med Chem 50:74–82PubMedCrossRefGoogle Scholar
  56. 56.
    Venhorst J, Nunez S, Terpstra JW, Kruse CG (2008). J Med Chem 51:3222–3229PubMedCrossRefGoogle Scholar
  57. 57.
    Sheridan RP, McGaughey GB, Cornell WD (2008). J Comput Aided Mol Des 22:257–265PubMedCrossRefGoogle Scholar
  58. 58.
    Rush TS, Grant JA, Mosyak L, Nicholls A (2005). J Med Chem 48:1489–1495PubMedCrossRefGoogle Scholar
  59. 59.
    FRED v.3.2.0.2 OpenEye Scientific Software Inc. Santa Fe NM, USA www.eyesopen.com
  60. 60.
    McGann M (2011). J Chem Inf Model 51:578–596PubMedCrossRefGoogle Scholar
  61. 61.
    Sotriffer C, Stahl M (2003) In: Abraham DJ (ed) Docking and scoring functions/virtual screening. Wiley & Sons, New York, p 1Google Scholar
  62. 62.
    Henrich S, Feierberg I, Wang T, Blomberg N, Wade RC (2010). Proteins 78:135–153PubMedCrossRefGoogle Scholar
  63. 63.
    Meijer L, Skaltsounis AL, Magiatis P, Polychronopoulos P, Knockaert M, Leost M, Ryan XP, Vonica CA, Brivanlou A, Dajani R, Crovace C, Tarricone C, Musacchio A, Roe SM, Pearl L, Greengard P (2003). Chem Biol 10:1255–1266PubMedCrossRefGoogle Scholar
  64. 64.
    Ribas J, Bettayeb K, Ferandin Y, Knockaert M, Garrofé-Ochoa X, Totzke F, Schächtele C, Mester J, Polychronopoulos P, Magiatis P, Skaltsounis AL, Boix J, Meijer L (2006). Oncogene 25:6304–6318PubMedCrossRefGoogle Scholar
  65. 65.
    Olesen PH, Sørensen AR, Ursø B, Kurtzhals P, Bowler AN, Ehrbar U, Hansen BF (2003). J Med Chem 46:3333–3341PubMedCrossRefGoogle Scholar
  66. 66.
    Kaidanovich-Beilin O, Woodgett JR (2011). Front Mol Neurosci 4:40PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Meijer L, Flajolet M, Greengard P (2004). Trends Pharmacol Sci 25:471–480PubMedCrossRefGoogle Scholar
  68. 68.
    Bain J, McLauchlan H, Elliot M, Cohen P (2003). Biochem J 371:199–204PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    FILTER v.2.5.1.4 OpenEye Scientific Software Inc. Santa Fe, NM USA www.eyesopen.com
  70. 70.
    Egan WJ, Merz KM, Baldwin JJ (2000). J Med Chem 43:3867–3877PubMedCrossRefGoogle Scholar
  71. 71.
    Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kipple KD (2002). J Med Chem 45:2615–2623PubMedCrossRefGoogle Scholar
  72. 72.
    Martin YC (2005). J Med Chem 48:3164–3170PubMedCrossRefGoogle Scholar
  73. 73.
    Schrödinger Release 2016–1: LigPrep v.3.1 (2016) Schrödinger, LLC, New York, NYGoogle Scholar
  74. 74.
    Schrödinger Release 2016–1: Maestro v.10.5 (2016) Schrödinger, LLC, New York, NYGoogle Scholar
  75. 75.
    Make Receptor v.3.2.0.2 OpenEye Scientific Software Inc., Santa Fe NM, USA www.eyesopen.com
  76. 76.
    Nicholls A, McGaughey GB, Sheridan RP, Good AC, Warren G, Mathieu M, Muchmore SW, Brown SP, Grant JA, Haigh JA, Nevins N, Jain AN, Kelley B (2010). J Med Chem 53:3862–3886PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Yan X, Li J, Liu Z, Zheng M, Ge H, Xu J (2013). J Chem Inf Model 53:1967–1978PubMedCrossRefGoogle Scholar
  78. 78.
    Fontaine F, Bolton E, Borodina Y, Bryant SH (2007). Chem Cent J 6:1–12Google Scholar
  79. 79.
    Muchmore SW, Debe DA, Metz JT, Brown SP, Martin YC, Hajduk PJ (2008). J Chem Inf Model 48:941–948PubMedCrossRefGoogle Scholar
  80. 80.
    Bortolato A, Perruccio F, Moro S (2011) In: Miteva MA (ed) Successful applications of in silico Approaches for lead/drug discovery, Bentham Science PublishersGoogle Scholar
  81. 81.
    Sutherland JJ, Nandigam RK, Erickson JA, Vieth M (2007). J Chem Inf Model 47:2293–2302PubMedCrossRefGoogle Scholar
  82. 82.
    Kelley BP, Brown SP, Warren GL, Muchmore SW (2015). J Chem Inf Model 55:1771–1780PubMedCrossRefGoogle Scholar
  83. 83.
    Bemis GW, Murcko MA (1996). J Med Chem 39:2887–2893PubMedCrossRefGoogle Scholar
  84. 84.
    Dassault Systèmes BIOVIA (2015) Discovery Studio Visualizer. v4.5.0, vol 15071. Dassault Systèmes, San Diego. www.3dsbiovia.com Google Scholar
  85. 85.
    Lu SY, Jiang YJ, Lv J, Zou JW, Wu TX (2011). J Comput Chem 32:1907–1918PubMedCrossRefGoogle Scholar
  86. 86.
    Zhang B, Tan VBC, Lim KM, Tay TE (2007). J Chem Inf Model 47:1877–1885PubMedCrossRefGoogle Scholar
  87. 87.
    Tirado-Rives J, Jorgensen WL (2006). J Med Chem 49:5880–5884PubMedCrossRefGoogle Scholar
  88. 88.
    Chang CA, Chen W, Gilson MK (2007). Proc Natl Acad Sci USA 104:1534–1539PubMedCrossRefGoogle Scholar
  89. 89.
    Duca JS, Madison VS, Voigt JH (2008). J Chem Inf Model 48:659–668PubMedCrossRefGoogle Scholar
  90. 90.
    Sadowski J, Gasteiger J, Klebe G (1994). J Chem Inf Comput Sci 34:1000–1008CrossRefGoogle Scholar
  91. 91.
    Boström J, Hogner A, Schmitt S (2006). J Med Chem 49:6716–6725PubMedCrossRefGoogle Scholar
  92. 92.
    Kramer T, Schmidt B, Lo Monte F (2012). Int J Alzheimers Dis 2012:381029Google Scholar
  93. 93.
    Chohan TA, Qian H-Y, Pan Y-L, Chen J-Z (2015). Mol BioSyst 12:145–161CrossRefGoogle Scholar
  94. 94.
    ChemSpider http://www.chemspider.com/ (accessed on July 2018)
  95. 95.
    SureChem http://www.surechem.com/ (accessed on July 2018)
  96. 96.
    Segraves NL, Robinson SJ, Garcia D, Said SA, Fu X, Schmitz FJ, Pietraszkiewicz H, Valeriote FA, Crews P (2004). J Nat Prod 67:783–792PubMedCrossRefGoogle Scholar
  97. 97.
    Kim HM, Kim C-S, Lee J-H, Jang SJ, Hwang JJ, Ro S, Choi J (2013). PLoS ONE 8:e60383PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Gustin JP, Karakas B, Weiss MB, Abukhdeir AM, Lauring J, Garay JP, Cosgrove D, Tamaki A, Konishi H, Konishi Y, Mohseni M, Wang G, Rosena DM, Denmeade SR, Higgins MJ, Vitolo MI, Bachman KE, Park BH (2009). Proc Natl Acad Sci U S A 106:2835–2840PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Kunnimalaiyaan S, Schwartz VK, Alao Jackson I, Gamblin TC, Kunnimalaiyaan M (2018). BMC Cancer 18:560–567PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Liliana Pacureanu
    • 1
  • Sorin Avram
    • 1
  • Alina Bora
    • 1
  • Ludovic Kurunczi
    • 1
  • Luminita Crisan
    • 1
  1. 1.Institute of Chemistry Timisoara of the Romanian AcademyTimisoaraRomania

Personalised recommendations