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Discovery of new PKN2 inhibitory chemotypes via QSAR-guided selection of docking-based pharmacophores

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Abstract

Serine/threonine-protein kinase N2 (PKN2) plays an important role in cell cycle progression, cell migration, cell adhesion and transcription activation signaling processes. In cancer, however, it plays important roles in tumor cell migration, invasion and apoptosis. PKN2 inhibitors have been shown to be promising in treating cancer. This prompted us to model this interesting target using our QSAR-guided selection of docking-based pharmacophores approach where numerous pharmacophores are extracted from docked ligand poses and allowed to compete within the context of QSAR. The optimal pharmacophore was sterically-refined, validated by receiver operating characteristic (ROC) curve analysis and used as virtual search query to screen the National Cancer Institute (NCI) database for new promising anti-PKN2 leads of novel chemotypes. Three low micromolar hits were identified with IC50 values ranging between 9.9 and 18.6 µM. Pharmacological assays showed promising cytotoxic properties for active hits in MTT and wound healing assays against MCF-7 and PANC-1 cancer cells.

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Abbreviations

PKN2:

Protein kinase N2

ATP:

Adenosine triphosphate

QSAR:

Quantitative structure activity relationship

ROC:

Receiver operating characteristic

IC50 :

Inhibitor concentration that causes 50% enzyme inhibition

MTT:

4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide

GA/MLR:

Genetic algorithm/Multiple linear regression

AUC:

Area under the curve

Hbic:

Hydrophobic

HBA:

Hydrogen bond acceptor

HBD:

Hydrogen bond donor

PosIon:

Positive ionizable feature

SNC:

Sensitivity

SPC:

Specificity

ACC:

Accuracy

MCF7:

Breast cancer cell line

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Acknowledgements

The authors thank the Deanships of Scientific Research at the Zarqa University and The University of Jordan for funding this project. We are greatly thankful for National Cancer Institute for the free NCI compounds gift. We appreciate the efforts of Ms. Haneen Sallam and Ms. Walaa Wahdan for the work in the tissue culture laboratory, help in media preparation, culturing the cancerous cells and sample preparation.

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Zarqa University,6-2020,Mahmoud A Al-Sha'er

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Authors and Affiliations

  1. Faculty of Pharmacy, Zarqa University, P.O. Box 132222, Zarqa, 13132, Jordan

    Mahmoud A. Al-Sha’er & Haneen A. Basheer

  2. Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman, Jordan

    Mutasem O. Taha

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  1. Mahmoud A. Al-Sha’er
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  3. Mutasem O. Taha
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Al-Sha’er, M.A., Basheer, H.A. & Taha, M.O. Discovery of new PKN2 inhibitory chemotypes via QSAR-guided selection of docking-based pharmacophores. Mol Divers 27, 443–462 (2023). https://doi.org/10.1007/s11030-022-10434-4

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