P450-Base Drug Interactions with Low Spin Drugs

这个项目的长期目标是了解药物和药物之间的详细相互作用 血红素组的细胞色素P450，以便更好地管理药物与药物的相互作用。细胞色素P50s 环磷酰胺(Cyps)是一种含血红素的酶，在药物代谢中起着至关重要的作用 互动。此外，环磷酰胺也是治疗乳腺癌、真菌感染和传染病的药物靶点。 几乎所有针对Cyps的药物，以及大多数具有其他靶点的新药都是由Cyps代谢的， 包括含氮杂环化合物。这些和其他含氮碎片被认为提供了 与细胞色素P450的关键相互作用导致抑制药物相互作用。氮的相互作用 含有CYP血红素辅因子的片段导致光谱变化，历史上被解释为 直接的血红素氮连接，这预计会导致高还原潜力，从而阻止催化 活动；这种交互是以CYP为目标的dnjgs的设计组件，它们在其他 最大限度减少药物相互作用的药物。然而，我们最近发现，一些含氮药物确实 不是直接与亚铁血红素连接，而是与留在亚铁血红素上的水发生氢键作用 改变了历史范式。由此产生的水桥药物复合体，曾经被认为是唯一的 抑制性物质被催化代谢。抗丙型肝炎病毒dmg的替拉帕韦是这一新的候选药物 而装订模式也将成为研究的重点。进一步了解决定经济增长的因素 络合物的形成及其功能性质是设计不受欢迎的药物所必需的 相互作用和优化CYP靶向治疗的药物设计。这个项目的目的是 确定不同药物和CYP亚型之间的这些相互作用的范围，以确定 的泛函性质。被识别的水桥络合物，并将这些鳍状物与 推测的水桥Telapvir-CyP3A4复合体的行为。 相关性(请参阅说明)： 细胞色素P45ps(Cyps)的药物代谢导致药物相互作用不良。更好的 了解不同类型的药物与细胞色素P450的血红素辅因子相互作用的方式将会有所改善 我们预测或控制药物相互作用的能力。

The long term goals of this project are to understand the the detailed interactions between drugs and the heme group of cytochrome P450s, in order to better manage drug-drug interactions. Cytochrome P50s (CYPs) are heme-containing enzymes that dominate drug metabolism and play a critical role in drug-drug interactions. In addition CYPs are drug targets for breast cancer, fungal infections and infectious diseases. Nearly all drugs targeted to CYPs, and most new drugs with other targets that are metabolized by CYPs, Include nitrogen heterocycles. These and other nitrogen-containing fragments are thought to provide the critical interactions with the CYPs that result in inhibitory drug interactions. Interactions ofthe nitrogen fragments with the CYP heme cofactor results in spectral changes that have historically been interpreted as direct heme-nitrogen ligation, which is expected to result in a high reduction potential that prevents catalytic activity; Such interactions are a design component of CYP-targeted dnjgs and they are avoided in other drugs to minimize drug interactions. However, our recent discovery that some nitrogen-containing drugs do not ligate directly to the heme, but instead they hydrogen bond to water remaining on the heme significantly changes the historical paradigm. The resulting water-bridged drug complexes, once thought to be solely inhibitory, are catalytically metabolized. The anti-hepatitus C dmg Telaprevir is candidate for this new binding mode and will be a focus of research. Further Understanding of the factors that determine the formation of the complexes, and the their functional properties, is necessary to engineer undesired drug-drug interactions and to optimize drug design of CYP-targeted therapeutics. The aims of this project are to determine the scope of these interactions among various drugs and cYP isoforms, to determine the fucntional properties of the. water-bridged complexes that are indentified, and to relate these findigns to the behavior of the putative water-bridged Telaprevir-CYP3A4 complex. RELEVANCE (See instructions): Drug metabolism by Cytochrome P45ps (CYPs) leads to undesirable drug interactions. A better understanding of the way that different types of drugs interact with the heme cofactor of CYPs will improve our ability to predict or control drug interactions.