Journal
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Volume 29, Issue 6, Pages 561-581Publisher
SPRINGER
DOI: 10.1007/s10822-015-9848-1
Keywords
Check point kinase 1; k nearest neighbor; dbCICA; Pharmacophore; In silico mining
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Funding
- Deanship of Scientific Research
- Hamdi-Mango Center for Scientific Research at the University of Jordan
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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 A mu M.
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