Determinants of Ligand Binding to cAMP-Dependent Protein Kinase

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• 作者：Philippe H. Hü ; nenberger ; Volkhard Helms ; Narendra Narayana ; Susan S. Taylor ; and J. Andrew McCammon
• 刊名：Biochemistry
• 出版年：1999
• 出版时间：February 23, 1999
• 年：1999
• 卷：38
• 期：8
• 页码：2358 - 2366
• 全文大小：250K
• 年卷期：v.38,no.8(February 23, 1999)
• ISSN：1520-4995

文摘

Protein kinases are essential for the regulation of cellular growth and metabolism. Since theirdysfunction leads to debilitating diseases, they represent key targets for pharmaceutical research. Therational design of kinase inhibitors requires an understanding of the determinants of ligand binding tothese proteins. In the present study, a theoretical model based on continuum electrostatics and a surface-area-dependent nonpolar term is used to calculate binding affinities of balanol derivatives, H-seriesinhibitors, and ATP analogues toward the catalytic subunit of cAMP-dependent protein kinase (cAPK orprotein kinase A). The calculations reproduce most of the experimental trends and provide insight intothe driving forces responsible for binding. Nonpolar interactions are found to govern protein-ligand affinity.Hydrogen bonds represent a negligible contribution, because hydrogen bond formation in the complexrequires the desolvation of the interacting partners. However, the binding affinity is decreased if hydrogen-bonding groups of the ligand remain unsatisfied in the complex. The disposition of hydrogen-bondinggroups in the ligand is therefore crucial for binding specificity. These observations should be valuableguides in the design of potent and specific kinase inhibitors.