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Molecular Diversity

, Volume 21, Issue 1, pp 187–200 | Cite as

Discovery of potent NEK2 inhibitors as potential anticancer agents using structure-based exploration of NEK2 pharmacophoric space coupled with QSAR analyses

  • Mohammad A. Khanfar
  • Fahmy Banat
  • Shada Alabed
  • Saja Alqtaishat
Original Article

Abstract

High expression of Nek2 has been detected in several types of cancer and it represents a novel target for human cancer. In the current study, structure-based pharmacophore modeling combined with multiple linear regression (MLR)-based QSAR analyses was applied to disclose the structural requirements for NEK2 inhibition. Generated pharmacophoric models were initially validated with receiver operating characteristic (ROC) curve, and optimum models were subsequently implemented in QSAR modeling with other physiochemical descriptors. QSAR-selected models were implied as 3D search filters to mine the National Cancer Institute (NCI) database for novel NEK2 inhibitors, whereas the associated QSAR model prioritized the bioactivities of captured hits for in vitro evaluation. Experimental validation identified several potent NEK2 inhibitors of novel structural scaffolds. The most potent captured hit exhibited an \(\hbox {IC}_{50}\) value of 237 nM.

Keywords

NEK2 QSAR Pharmacophore cancer 

Abbreviations

AML

Acute myeloid leukemia

GFA

Genetic function algorithm

MLR

Multiple linear regression

NCI

National Cancer Institute

NEK2

Never in mitosis (NIMA)-related kinase 2

NIMA

Never in mitosis

ROC

Receiver operating characteristic

Notes

Acknowledgments

The authors thank the Deanship of Scientific Research at the University of Jordan for their generous funds. We are also thankful for NCI institution for supporting us with free samples. We are thankful for Prof. Mutasem Taha at Faculty of Pharmacy, University of Jordan for fruitful discussions and insight ideas.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11030_2016_9696_MOESM1_ESM.docx (714 kb)
Supplementary Materials The detailed theoretical and experimental procedures of pharmacophoric and QSAR modeling, and analytical data of active hits discovered in this study. (doc 715 KB)

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Mohammad A. Khanfar
    • 1
    • 2
  • Fahmy Banat
    • 1
  • Shada Alabed
    • 1
  • Saja Alqtaishat
    • 1
  1. 1.Department of Pharmaceutical sciences, Faculty of PharmacyThe University of JordanAmmanJordan
  2. 2.Institut fuer Pharmazeutische and Medizinische ChemieHeinrich-Heine-Universitaet DuesseldorfDuesseldorfGermany

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