Journal of Computer-Aided Molecular Design

, Volume 29, Issue 6, pp 561–581 | Cite as

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

  • Nour Jamal Jaradat
  • Mohammad A. Khanfar
  • Maha Habash
  • Mutasem Omar Taha
Article
First Online:
Received:
Accepted:

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.

Keywords

Check point kinase 1 k nearest neighbor dbCICA Pharmacophore In silico mining 
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Notes

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.).

Supplementary material

10822_2015_9848_MOESM1_ESM.doc (6.4 mb)
Supplementary material 1 (DOC 6583 kb)

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Nour Jamal Jaradat
    • 1
  • Mohammad A. Khanfar
    • 2
  • Maha Habash
    • 3
  • Mutasem Omar Taha
    • 2
  1. 1.Faculty of PharmacyZarqa UniversityZarqaJordan
  2. 2.Department of Pharmaceutical Sciences, Faculty of PharmacyThe University of JordanAmmanJordan
  3. 3.Faculty of PharmacyApplied Sciences UniversityAmmanJordan

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