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：
9120388
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 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9120388
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 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 novel therapeutics optical spectra oxidation prevent pyrazinoic acid pyridine quinoline targeted treatment theories

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与毒品之间的详细互动血红素组的细胞色素P450，以更好地管理药物相互作用。细胞色素P50 （CYP）是含血红素的酶，主导药物代谢并在药物中起关键作用互动。此外，CYP是用于乳腺癌，真菌感染和传染病的药物靶标。几乎所有针对CYP的药物，以及大多数由CYPS代谢的其他靶标的新药，包括氮杂环。这些和其他含氮的碎片被认为提供了与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血红素辅因子的碎片导致光谱变化历史上被解释为直接的血红素氮连接，预计会导致高还原电位，从而防止催化活动;这种相互作用是CYP靶向DNJG的设计组成部分，并且在其他方面避免了它们药物以最大程度地减少药物相互作用。但是，我们最近发现某些含氮药物会不是直接与血红素结合，而是将其氢键氢氢与血红素上的水结合在一起改变历史范式。由此产生的水桥综合体，曾经被认为是完全抑制性，被催化代谢。反hepatitus c dmg telaprevir是这一新的候选人绑定模式，将成为研究的重点。进一步了解决定的因素对于工程不希望的药物，必须形成复合物及其功能性能相互作用并优化CYP靶向治疗剂的药物设计。该项目的目的是确定各种药物和CYP同工型之间这些相互作用的范围，以确定诱导特性。水框的配合物，并将这些发现与推定的水框telaprevir-CYP3A4复合物的行为。相关性（请参阅说明）：细胞色素P45PS（CYPS）的药物代谢导致不良药物相互作用。更好了解不同类型的药物与CYP的血红素辅因子相互作用的方式将改善我们预测或控制药物相互作用的能力。