P450-Base Drug Interactions with Low Spin Drugs

P450 基药物与低自旋药物的相互作用

基本信息

批准号：
8740514
负责人：
WILLIAM M ATKINS
金额：
$ 42.47万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-25 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8740514
关键词：
Active Sites Amines Antifungal Agents Behavior Binding CYP2C19 gene CYP2C9 gene CYP3A4 gene Catalysis Communicable Diseases Complex Consumption Cytochrome P450 Cytochromes Data Drug Design Drug Interactions Drug Targeting Electron Transport Electrons Engineering Enzymes Fluconazole Goals Heme Heme Group Heme Iron Hepatitis C virus Hydrogen Bonding Hydrogen Peroxide Instruction Itraconazole Ligands Ligation Measures Metabolic Metabolism Mycoses NADP Nitrogen Optics Oxidation-Reduction Oxidoreductase Pharmaceutical Preparations Play Property Protease Inhibitor Protein Isoforms Pyrazines Relative (related person)Research Ritonavir Role Source Spectrum Analysis Structure Techniques Testosterone Thiazoles Triazoles Water analog base cofactor density design drug metabolism improved inhibitor/antagonist malignant breast neoplasm oxidation prevent pyrazinoic acid pyridine quinoline theories therapeutic target

项目摘要

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.

该项目的长期目标是了解药物和药物之间的详细相互作用细胞色素 P450 的血红素组，以便更好地管理药物间相互作用。细胞色素P50 （CYP）是含血红素的酶，主导药物代谢并在药物间发挥关键作用互动。此外，CYP 也是乳腺癌、真菌感染和传染病的药物靶点。几乎所有以 CYP 为靶点的药物，以及大多数具有由 CYP 代谢的其他靶点的新药，包括氮杂环。这些和其他含氮片段被认为提供与 CYP 的关键相互作用导致抑制性药物相互作用。氮的相互作用带有 CYP 血红素辅助因子的片段会导致光谱变化，历史上被解释为直接血红素-氮连接，预计会产生高还原电位，从而阻止催化活动;这种相互作用是 CYP 目标 dnjgs 的设计组成部分，并且在其他药物以尽量减少药物相互作用。然而，我们最近发现一些含氮药物确实不直接与血红素连接，而是与血红素上剩余的水形成氢键改变历史范式。由此产生的水桥药物复合物曾经被认为是唯一的抑制性，催化代谢。抗丙型肝炎药物 Telaprevir 是这一新药物的候选药物结合方式将成为研究的热点。进一步了解决定因素复合物的形成及其功能特性对于设计不需要的药物是必要的相互作用并优化 CYP 靶向疗法的药物设计。该项目的目标是确定各种药物和 cYP 亚型之间相互作用的范围，以确定的功能特性。已识别的水桥复合物，并将这些发现与假定的水桥特拉匹韦-CYP3A4 复合物的行为。相关性（参见说明）：细胞色素 P45ps (CYP) 的药物代谢会导致不良的药物相互作用。更好的了解不同类型的药物与 CYP 血红素辅因子相互作用的方式将得到改善我们预测或控制药物相互作用的能力。