Cyclic Peptides as Protein Kinase Inhibitors: Structure-Activity Relationship and Molecular Modeling
| Autor: | Saghar Mozaffari, Samara E Hanna, Rakesh Tiwari, Michel F. Sanner, Simin Rahighi, Keykavous Parang, Khalid Zoghebi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Stereochemistry
General Chemical Engineering Peptide Library and Information Sciences Molecular Dynamics Simulation 01 natural sciences Peptides Cyclic Article src Homology Domains Structure-Activity Relationship 0103 physical sciences Bruton's tyrosine kinase Humans Amino Acid Sequence Kinase activity Binding site Protein kinase A Protein Kinase Inhibitors chemistry.chemical_classification 010304 chemical physics biology Kinase Cyclin-dependent kinase 2 General Chemistry Cyclic peptide 0104 chemical sciences Computer Science Applications 010404 medicinal & biomolecular chemistry chemistry biology.protein Protein Binding |
| Zdroj: | J Chem Inf Model |
| Popis: | Under-expression or over-expression of protein kinases has been shown to be associated with unregulated cell signal transduction in cancer cells. Therefore, there is a major interest in designing protein kinase inhibitors as anticancer agents. We have previously reported [WR](5), a peptide containing alternative arginine (R) and tryptophan (W) residues as a non-competitive c-Src tyrosine kinase inhibitor. A number of larger cyclic peptides containing alternative hydrophobic and positively charged residues [WR](x) (x = 6–9), and hybrid cyclic-linear peptides, [R(6)K]W(6) and [R(5)K]W(7), containing R and W residues were evaluated for their protein kinase inhibitory potency. Among all the peptides, cyclic peptide [WR](9) was found to be the most potent tyrosine kinase inhibitor. [WR](9) showed higher inhibitory activity (IC(50)= 0.21 μM) than [WR](5), [WR](6), [WR](7), and [WR](8) with IC(50) values of 0.81, 0.57, 0.35, and 0.33 μM, respectively, against Src kinase as determined by a radioactive assay using [γ-(33)P]ATP. Consistent with the result above, [WR](9) inhibited other protein kinases such as Abl kinase activity with an IC(50) value of 0.35 μM, showing 2.2-fold higher inhibition than [WR](5) (IC(50)= 0.79 μM). [WR](9) also inhibited PKCa kinase activity with an IC(50) value of 2.86 μM, approximately 3-fold higher inhibition than [WR](5) (IC(50)=8.52 μM). A similar pattern was observed against Braf, c-Src, Cdk2/Cyclin A1, and Lck. [WR](9) exhibited IC(50) values of |
| Databáze: | OpenAIRE |
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