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


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.


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



Glycogen synthase kinase-3


Cyclin-dependent kinases-2


Mitogen-activated protein kinase


CDC-like kinase


Adenosine triphosphate


CDK-2 weak inhibitors and inactive dataset

CDK-2 decoys

DUD-E CDK-2 decoys dataset


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


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


Tanimoto combo


Shape Tanimoto


Scaled color


Combo score





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)


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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

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