Mechanisms of Atypical Drug Kinetics and Interactions

非典型药物动力学和相互作用的机制

• 批准号: 7061796
• 负责人: TIMOTHY S. TRACY
• 金额: $ 23.81万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061796
• 关键词: active sites; chemical models; clinical research; computer simulation; conformation; cytochrome P450; drug design /synthesis /production; drug interactions; drug metabolism; enzyme activity; enzyme mechanism; enzyme structure; enzyme substrate complex; heme; isozymes; mathematical model; model design /development; nuclear magnetic resonance spectroscopy; pharmacogenetics; pharmacokinetics; protein structure function; site directed mutagenesis

DESCRIPTION (PROVIDED BY APPLICANT): Atypical kinetic profiles observed with drug metabolizing enzymes, such as the cytochromes P450, can confound in vitro determinations of kinetic parameter estimates. During the development of new drug entities, inaccurate kinetic parameter estimates can lead to incorrect decisions as to the potential success of the drug compound. The long term goals of this research are to understand the biochemical mechanisms resulting in atypical kinetic profiles and develop computer models capable of predicting the occurrence of atypical kinetics. It is generally accepted that two (or more) substrate molecules can bind within the active site of cytochrome P450 enzymes and this phenomenon plays a role in atypical kinetics. NMR work from our laboratory has demonstrated two molecules present in the active site and the presence of an effector causes movement of the primary substrate closer to the heme. Increases in P450 reaction efficiency and reductions in reaction cycle uncoupling also have been observed during CYP2C9 heteroactivation, but preliminary data suggest that not all activator compounds act by the same mechanism. The structure-activity basis for these differential effects is unknown. More recently, we have observed that genetic variants of CYP2C9 exhibit greater degrees of heteroactivation than wild-type enzyme, suggesting that enzyme conformation may also be a factor in the observation of atypical kinetics. The current competing renewal builds upon the above findings and seeks to ascertain; a) the mechanism(s) by which effector molecules alter P450 reaction cycle efficiency and the structure-activity relationships of molecules causing these effects, b) the changes in substrate-heme iron distances and substrate orientation produced by different effectors, and c) how enzyme amino acid alterations affect substrate/effector-protein interactions and thus, activation. From these data, computer models will be developed to predict the occurrence of atypical kinetics and potential drug interactions to assist in the drug development process.

描述（由申请人提供）：与药物代谢酶（例如细胞色素p450）观察到的非典型动力学特征可以在体外确定动力学参数估计值。在新药物实体的开发过程中，不准确的动力学参数估计可能会导致对药物化合物潜在成功的错误决定。这项研究的长期目标是了解导致非典型动力学轮廓的生化机制，并开发能够预测非典型动力学发生的计算机模型。人们普遍认为，两个（或更多）底物分子可以在细胞色素P450酶的活性位点结合，并且该现象在非典型动力学中起作用。来自我们实验室的NMR工作表明，活性位点存在两个分子，并且效应子的存在导致靠近血红素的主要基质的运动。 P450反应效率的提高和在CYP2C9异性激活过程中也观察到了反应周期解偶联的降低，但是初步数据表明，并非所有激活剂化合物都通过相同的机制起作用。这些差异效应的结构活动基础尚不清楚。最近，我们观察到，与野生型酶相比，CYP2C9的遗传变异表现出更大的异质活化程度，这表明酶构象也可能是观察非典型动力学的一个因素。当前的竞争更新是基于上述发现并寻求确定的； a）效应分子改变P450反应周期效率的机制以及引起这些作用的分子的结构 - 活性关系，b）底物 - - - 血液 - 铁距离和不同效应子产生的底物方向的变化，以及c）酶氨基酸的改变如何影响糖/效应效应效应 - 效应效果蛋白相互作用和因此。从这些数据中，将开发计算机模型来预测非典型动力学和潜在药物相互作用的发生，以帮助药物开发过程。