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.
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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
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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.
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The authors declare that they have no conflict of interest.
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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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Khanfar, M.A., Banat, F., Alabed, S. et al. Discovery of potent NEK2 inhibitors as potential anticancer agents using structure-based exploration of NEK2 pharmacophoric space coupled with QSAR analyses. Mol Divers 21, 187–200 (2017). https://doi.org/10.1007/s11030-016-9696-5
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DOI: https://doi.org/10.1007/s11030-016-9696-5