Hünenberger P H, Helms V, Narayana N, Taylor S S, McCammon J A
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla 92093-0365, USA.
Biochemistry. 1999 Feb 23;38(8):2358-66. doi: 10.1021/bi982064g.
Protein kinases are essential for the regulation of cellular growth and metabolism. Since their dysfunction leads to debilitating diseases, they represent key targets for pharmaceutical research. The rational design of kinase inhibitors requires an understanding of the determinants of ligand binding to these 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-series inhibitors, and ATP analogues toward the catalytic subunit of cAMP-dependent protein kinase (cAPK or protein kinase A). The calculations reproduce most of the experimental trends and provide insight into the 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 complex requires 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-bonding groups in the ligand is therefore crucial for binding specificity. These observations should be valuable guides in the design of potent and specific kinase inhibitors.
蛋白激酶对于细胞生长和代谢的调节至关重要。由于其功能障碍会导致使人衰弱的疾病，它们成为药物研究的关键靶点。激酶抑制剂的合理设计需要了解配体与这些蛋白质结合的决定因素。在本研究中，基于连续介质静电学和表面积依赖性非极性项的理论模型被用于计算巴拉诺醇衍生物、H系列抑制剂和ATP类似物对环磷酸腺苷依赖性蛋白激酶（cAPK或蛋白激酶A）催化亚基的结合亲和力。计算结果重现了大部分实验趋势，并深入了解了负责结合的驱动力。发现非极性相互作用决定蛋白质-配体亲和力。氢键的贡献可忽略不计，因为复合物中的氢键形成需要相互作用伙伴的去溶剂化。然而，如果配体的氢键基团在复合物中未得到满足，则结合亲和力会降低。因此，配体中氢键基团的排列对于结合特异性至关重要。这些观察结果应该是设计强效和特异性激酶抑制剂的有价值指导。
