P450-Base Drug Interactions with Low Spin Drugs

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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.