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In Silico Pharmacology

, 6:5 | Cite as

Computer aided drug design based on 3D-QSAR and molecular docking studies of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amine derivatives as PIM2 inhibitors: a proposal to chemists

  • Adnane Aouidate
  • Adib Ghaleb
  • Mounir Ghamali
  • Samir Chtita
  • Abdellah Ousaa
  • M’barek Choukrad
  • Abdelouahid Sbai
  • Mohammed Bouachrine
  • Tahar Lakhlifi
Original Research
  • 40 Downloads

Abstract

PIM2 kinase plays a crucial role in the cell cycle events including survival, proliferation, and differentiation in normal and neoplastic neuronal cells. Thus, it is regarded as an essential target for cancer pharmaceutical. Design of novel 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amine derivatives with enhanced PIM2 inhibitory activity. A series of twenty-five PIM2 inhibitors reported in the literature containing 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines scaffold was studied by using two computational techniques, namely, three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indexes analysis (CoMSIA) studies were developed using nineteen molecules having pIC50 ranging from 8.222 to 4.157. The best generated CoMFA and CoMSIA models exhibit conventional determination coefficients R2 of 0.91 and 0.90 as well as the Leave One Out cross-validation determination coefficients Q2 of 0.68 and 0.62, respectively. Moreover, the predictive ability of those models was evaluated by the external validation using a test set of six compounds with predicted determination coefficients R test 2 of 0.96 and 0.96, respectively. Besides, y-randomization test was also performed to validate our 3D-QSAR models. The most and the least active compounds were docked into the active site of the protein (PDB ID: 4 × 7q) to confirm those obtained results from 3D-QSAR models and elucidate the binding mode between this kind of compounds and the PIM2 enzyme. These satisfactory results are not offered help only to understand the binding mode of 5-(1H-indol-5-yl)-1,3,4-thiadiazol series compounds into this kind of targets, but provide information to design new potent PIM2 inhibitors.

Keywords

CoMFA CoMSIA Molecular docking PIM2 Drug design 5-(1H-indol-5-yl)-1,3,4-thiadiazol 

Notes

Acknowledgment

We are grateful to the “Association Marocaine des Chimistes Théoriciens” (AMCT) and “Moroccan centre of scientific and technique research” (CNRST) for their pertinent help concerning the programs.

Compliance with ethical standards

Competing interests

The authors declare that they have no competing interests.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Adnane Aouidate
    • 1
  • Adib Ghaleb
    • 1
  • Mounir Ghamali
    • 1
  • Samir Chtita
    • 1
  • Abdellah Ousaa
    • 1
  • M’barek Choukrad
    • 1
  • Abdelouahid Sbai
    • 1
  • Mohammed Bouachrine
    • 2
  • Tahar Lakhlifi
    • 1
  1. 1.MCNSL, School of SciencesMoulay Ismail UniversityMeknesMorocco
  2. 2.High School of TechnologyMoulay Ismail UniversityMeknesMorocco

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