Healy Eamonn F, Johnson Skylar, Hauser Charles R, King Peter J
Department of Chemistry, St. Edward's University, Austin, TX 78704, USA.
FEBS Lett. 2009 Sep 3;583(17):2899-906. doi: 10.1016/j.febslet.2009.07.051. Epub 2009 Aug 4.
The conformational flexibility exhibited by protein kinases poses an enormous challenge to the design of cancer therapeutics. Additionally the high degree of structural conservation within the kinase superfamily often leads to inhibitors that exhibit little selectivity and substantial cross reactivity. This work investigates the conformational changes that accompany the binding of Gleevec, or imatinib mesylate, to the tyrosine kinases c-Kit and c-Abl. Our analysis is that this fit is driven, at least in part, by the need to exclude water from solvent-exposed backbone hydrogen bonds. Both experimental and molecular modeling studies of the active state inhibitor of the tyrosine kinase c-Abl indicate that solvent exclusion also plays a role in this system.
蛋白激酶所展现出的构象灵活性给癌症治疗药物的设计带来了巨大挑战。此外，激酶超家族内部高度的结构保守性常常导致抑制剂的选择性较差且具有显著的交叉反应性。这项研究调查了格列卫（即甲磺酸伊马替尼）与酪氨酸激酶c-Kit和c-Abl结合时所伴随的构象变化。我们的分析认为，这种契合至少部分是由将水排除在溶剂暴露的主链氢键之外的需求所驱动的。对酪氨酸激酶c-Abl活性状态抑制剂的实验和分子建模研究均表明，溶剂排除在该系统中也发挥了作用。
