P450-Base Drug Interactions with Low Spin Drugs

P450 基药物与低自旋药物的相互作用

• 批准号: 8716902
• 负责人: WILLIAM M ATKINS
• 金额: $ 45.19万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/8716902
• 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

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。 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 细胞色素氧化酶（CYP）是一类含血红素的酶，在药物代谢中起着重要作用， 交互.此外，CYP是乳腺癌、真菌感染和传染病的药物靶标。 几乎所有以CYP为靶点的药物，以及大多数以CYP代谢的其他靶点为靶点的新药， 包括氮杂环。这些和其他含氮碎片被认为提供了 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 具有血红素辅因子的片段导致光谱变化，历史上被解释为 直接血红素-氮连接，这预计会导致高还原电位，阻止催化还原。 活性;这种相互作用是CYP靶向dnjgs的设计组分，并且在其他药物中避免。 减少药物相互作用。然而，我们最近发现，一些含氮药物 不直接连接到血红素，而是氢键显着保留在血红素上的水 改变了历史的范式。由此产生的水桥药物复合物，曾经被认为是唯一的 抑制性的，被催化代谢。抗丙型肝炎病毒药物特拉匹韦是这种新的候选药物。 结合模式，将是一个重点研究。进一步了解决定性因素 复合物的形成及其功能特性对于工程化不期望的药物-药物组合物是必要的。 相互作用和优化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亚型之间相互作用的范围， 的功能特性。水桥复合物的鉴定，并将这些发现与 假定的水桥特拉匹韦-CYP 3A 4复合物的行为。 相关性（参见说明）： 通过细胞色素P45 ps（CYP）的药物代谢导致不期望的药物相互作用。更好的 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有助于提高 我们预测或控制药物相互作用的能力。