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

• 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
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/BF00124317

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.