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Combining docking-based comparative intermolecular contacts analysis and k-nearest neighbor correlation for the discovery of new check point kinase 1 inhibitors

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Abstract

Check point kinase 1 (Chk1) is an important protein in G2 phase checkpoint arrest required by cancer cells to maintain cell cycle and to prevent cell death. Therefore, Chk1 inhibitors should have potential as anti-cancer therapeutics. Docking-based comparative intermolecular contacts analysis (dbCICA) is a new three-dimensional quantitative structure activity relationship method that depends on the quality and number of contact points between docked ligands and binding pocket amino acid residues. In this presented work we implemented a novel combination of k-nearest neighbor/genetic function algorithm modeling coupled with dbCICA to select critical ligand-Chk1 contacts capable of explaining anti-Chk1 bioactivity among a long list of inhibitors. The finest set of contacts were translated into two valid pharmacophore hypotheses that were used as 3D search queries to screen the National Cancer Institute’s structural database for new Chk1 inhibitors. Three potent Chk1 inhibitors were discovered with IC50 values ranging from 2.4 to 69.7 µM.

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Acknowledgments

The authors thank the Deanship of Scientific Research and Hamdi-Mango Center for Scientific Research at the University of Jordan for their generous funds. The authors are also thankful to the National Cancer Institute for freely providing NCI hits. (Additional Supporting Information may be found in the online version of this article.).

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Authors and Affiliations

  1. Faculty of Pharmacy, Zarqa University, Zarqa, Jordan

    Nour Jamal Jaradat

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

    Mohammad A. Khanfar & Mutasem Omar Taha

  3. Faculty of Pharmacy, Applied Sciences University, Amman, Jordan

    Maha Habash

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  1. Nour Jamal Jaradat
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  2. Mohammad A. Khanfar
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  3. Maha Habash
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  4. Mutasem Omar Taha
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Correspondence to Mutasem Omar Taha.

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Jaradat, N.J., Khanfar, M.A., Habash, M. et al. Combining docking-based comparative intermolecular contacts analysis and k-nearest neighbor correlation for the discovery of new check point kinase 1 inhibitors. J Comput Aided Mol Des 29, 561–581 (2015). https://doi.org/10.1007/s10822-015-9848-1

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