Studies of targets of protein kinase inhibitors

蛋白激酶抑制剂靶点研究

• 批准号: 7033481
• 负责人: ADRIAN Hamilton ELCOCK
• 金额: $ 25.08万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033481
• 关键词: X ray crystallography; acidity /alkalinity; binding sites; calorimetry; computational biology; drug discovery /isolation; enzyme substrate complex; intermolecular interaction; kinase inhibitor; protein binding; small molecule; thermodynamics

DESCRIPTION (provided by applicant): The proposed research will be a combined experimental and computational study of the interactions between protein kinases and small molecule inhibitors. Protein kinases are implicated in a number of diseases, and are therefore attractive therapeutic targets. A major challenge however in designing small molecule inhibitors of kinases is how to develop inhibitors that specifically target a kinase of interest while leaving the hundreds of other kinases in the body unaffected. In order to achieve this goal, the factors that control the specificity of inhibitor-kinase interactions need to be understood, and one way to do this is to develop computational methodologies that can accurately predict the relative affinities of inhibitor-kinase complexes. The proposed research plan aims to test, extend and refine such a computational methodology through combination with a number of experimental studies. The specific aims involve: (1) Inhibition constants of commercially available small molecule inhibitors with a range of approximately 10 protein kinase targets will be measured. These studies will provide new quantitative data on inhibitor-kinase interactions. (2) The binding thermodynamics of inhibitor-kinase complexes will be measured with isothermal titration calorimetry. Separate measurements of binding free energies, enthalpies and entropies will be used to parameterize an energetic description of inhibitor-kinase binding interactions. (3) The crystal structures of inhibitors in complex with a range of different protein kinase targets will be solved. These studies will provide a direct and comprehensive view of the extent to which the binding orientations adopted by a given inhibitor change when complexed with different protein kinases. (4) The experimental data obtained from Aims 1-3 will be used to develop and test a computational method for accurately predicting the relative binding affinities of an inhibitor with all approximately 500 human protein kinases. Protein kinases, being implicated in a large number of different cancer types, are increasingly seen as very important targets for therapeutic drugs. The research proposed here directly addresses the single greatest challenge to the therapeutic pursuit of kinases: how to design small molecule inhibitors that can specifically inhibit a kinase of interest.

描述（由申请人提供）：拟议的研究将是对蛋白激酶与小分子抑制剂之间相互作用的合并实验和计算研究。蛋白激酶与多种疾病有关，因此是有吸引力的治疗靶标。然而，在设计小分子抑制剂时，一个主要的挑战是如何开发抑制剂，这些抑制剂专门针对感兴趣的激酶，同时将数百种其他激酶不受影响。为了实现这一目标，需要理解控制抑制剂 - 激酶相互作用的特异性的因素，而这样做的一种方法是开发可以准确预测抑制剂 - 激酶复合物的相对亲和力的计算方法。拟议的研究计划旨在通过结合许多实验研究来测试，扩展和完善这种计算方法。具体目的涉及：（1）将测量具有大约10个蛋白激酶靶标范围的市售小分子抑制剂的抑制常数。这些研究将提供有关抑制剂 - 激酶相互作用的新定量数据。 （2）将通过等温滴定量热法测量抑制剂 - 激酶络合物的结合热力学。结合自由能，焓和熵的单独测量将用于参数化抑制剂 - 激酶结合相互作用的能量描述。 （3）将解决与一系列不同蛋白激酶靶标的复合物中抑制剂的晶体结构。这些研究将提供直接而全面的观点，即当与不同蛋白激酶复合时，给定抑制剂会改变结合方向的程度。 （4）从AIMS 1-3获得的实验数据将用于开发和测试一种计算方法，以准确预测抑制剂与所有大约500个人类蛋白激酶的相对结合亲和力。蛋白激酶与大量不同的癌症类型有关，越来越被视为治疗药物的非常重要的靶标。这里提出的研究直接解决了对激酶治疗追求的最大挑战：如何设计可以专门抑制感兴趣激酶的小分子抑制剂。