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Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity
- Source :
- Molecules, Molecules, Vol 20, Iss 1, Pp 1176-1191 (2015), Volume 20, Issue 1, Pages 1176-1191
- Publication Year :
- 2015
- Publisher :
- MDPI, 2015.
-
Abstract
- Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant Tm shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt. Each one of these compounds was also validated by reducing the kinases activity by at least 25%. The binding sites for these compounds were identified by in silico docking at the ATP-binding site of the respective hNeks. Potential inhibitors were first screened by thermal shift assays, had their efficiency tested by a kinase assay, and were finally analyzed by molecular docking. Our findings corroborate the idea of ATP-competitive inhibition for hNek1 and hNek6 and suggest a novel non-competitive inhibition for hNek7 in regard to GSK-3 Inhibitor XIII. Our results demonstrate that our approach is useful for finding promising general and specific hNekscandidate inhibitors, which may also function as scaffolds to design more potent and selective inhibitors.
- Subjects :
- ATP-competitive inhibitors
Pharmaceutical Science
Cell Cycle Proteins
compound screening
Biology
Protein Serine-Threonine Kinases
Article
Analytical Chemistry
drug discovery
Substrate Specificity
lcsh:QD241-441
Non-competitive inhibition
lcsh:Organic chemistry
non-competitive inhibition
Humans
NIMA-Related Kinases
NIMA-Related Kinase 1
Physical and Theoretical Chemistry
Binding site
Protein kinase A
Protein Kinase Inhibitors
Drug discovery
Kinase
molecular modeling
Organic Chemistry
kinase assays
molecular docking
Molecular biology
Recombinant Proteins
Molecular Docking Simulation
Chemistry (miscellaneous)
Molecular Medicine
Phosphorylation
Neks
Subjects
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 20
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Molecules
- Accession number :
- edsair.doi.dedup.....812aaa6bc97c1a2fdb9e1400900b5b63