Modelling study of protein kinase inhibitors: binding mode of staurosporine and origin of the selectivity of CGP 52411

A model for the binding mode of the potent protein kinase inhibitor staurosporine is proposed. Using the information provided by the crystal structure of the cyclic-AMP-dependent protein kinase, it is suggested that staurosporine, despite a seemingly unrelated chemical structure, exploits the same k...

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Bibliographic Details
Published in:Journal of computer-aided molecular design 1995-12, Vol.9 (6), p.465-472
Main Authors: Furet, P, Caravatti, G, Lydon, N, Priestle, J P, Sowadski, J M, Trinks, U, Traxler, P
Format: Article
Language:English
Subjects:
Alkaloids - chemistry
Alkaloids - metabolism
Alkaloids - pharmacology
Binding Sites
Computer Simulation
Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors
Cyclic AMP-Dependent Protein Kinases - chemistry
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Hydrogen Bonding
Models, Molecular
Molecular Conformation
Molecular Structure
Phthalimides - chemistry
Phthalimides - metabolism
Phthalimides - pharmacology
Protein Conformation
Protein Kinase Inhibitors
Protein Kinases - chemistry
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - chemistry
Staurosporine
Thermodynamics
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Summary:A model for the binding mode of the potent protein kinase inhibitor staurosporine is proposed. Using the information provided by the crystal structure of the cyclic-AMP-dependent protein kinase, it is suggested that staurosporine, despite a seemingly unrelated chemical structure, exploits the same key hydrogen-bond interactions as ATP, the cofactor of the protein kinases, in its binding mode. The structure-activity relationship of the inhibitor and a docking analysis give strong support to this hypothesis. The selectivity of the dianilinophthalimide inhibitor CGP 52411 towards the EGF-receptor protein tyrosine kinase is rationalized on the basis of the model. It is proposed that this selectivity originates in the occupancy, by one of the anilino moieties of the inhibitor, of the region of the enzyme cleft that normally binds the ribose ring of ATP, which appears to possess a marked lipophilic character in this kinase.
ISSN:0920-654X
1573-4951
DOI:10.1007/BF00124317