Protein kinases libraries

Enzyme-adduct formation has also been successfully achieved with the Erbl and 2 (receptor tyrosine kinases from EGFR subfamily) [19, 20], suggesting that the tethered library-screening approach would also be amenable to protein kinases. 

Commensurately with the development of various catalyst systems, the Pd-catalyzed G-O cross-coupling has found a number of synthetic applications. Examples include the syntheses of the protein kinase G (PKC) activator (+)-decursin,104 the natural product heliannuol E,105 a chiral 2-methyl chroman,106 and a series of aryloxy and alkoxy porphyrins.107 The Buchwald-Hartwig coupling has also been utilized in the preparation of a heterocycle library.108 Intramolecular O-arylation has also been achieved in the reactions of enolates with aryl halides leading to benzofur-ans.109,110 Finally, a double cross-coupling between an 0-dibromobenzene and a glycol has also been applied for the preparation of benzodioxanes (Equation (16)).1... 

Triciribine, also known as Akt/protein kinase B signaling inhibitor-2 (API-2) compound 52, Fig. 9), was identified by screening the National Cancer Institute Diversity Set chemical library (1992 compounds). The screen was performed using a cell-based proliferation assay with PKB/1 transformed NIH3T3 cells, and triciribine scored positive in this assay with an IC50 value of 50 nM [ 196]. Although the compound blocks the cellular phosphorylation... 

The receptor relevance of BCUT descriptors has inspired several groups to apply them in conjunction with other methods. Beno and Mason reported the use of simulated annealing to optimize library design using BCUT chemistry space and four-point pharmacophores concurrently (33) and the use of chemistry spaces in conjunction with property profiles (52). The application of such composite methods to target class library design is readily apparent. Pirard and Pickett reported the application of the chemometric method, partial least squares discriminant analysis, with BCUT descriptors to successfully classify ATP-site-directed kinase inhibitors active against five different protein kinases... 

Knight, James D. R., Bin Qian, David Baker, and Rashmi Kothary. Conservation, Variability and the Modeling of Active Protein Kinases. Public Library of Science (PLoS) ONE, October 3, 2007. Available online. URL http //www.plosone.org/article/info%3Adoi%2Fl 0.1371%2 FJournal.pone.0000982. Accessed May 28,2009. The researchers compared some of the 518 known human protein kinases, and introduced an algorithm that may become useful in predicting their structures. 

Key words QSAR, Free-Wilson, MLR, virtual libraries, combinatorial chemistry, protein kinase,... 

Stahura, F. L., Xue, L., Godden, J. W., Bajorath, J. (1999) Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein kinases. /Mol Graph Model 17, 1-9, 51-52. 

Key words Protein kinase, kinase-targeted library, library design, kinase chemical cores, substructure search, SMARTS Query, subsetting, binding mode annotation. 

Radionuclide-based screening for protein kinase substrates is a quick and effective method for determining peptide substrates for protein kinases.28-31 The method presented here is based on the screening of random synthetic combinatorial peptide libraries with a protein kinase and is divided into two main parts (1) the phosphorylation of the peptide bead library and (2) the recovery and characterization of positive beads. 

Tegge, W., Frank, R., Hofmann, F., and Dostmann, R.G. (1995) Determination of cyclic nucleotide-dependent protein kinase substrate specificity by the use of peptide libraries on cellulose paper. Biochemistry 34, 10569-10577. 

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