Toxicological importance of CYP3A4 catalysis and inhibition
CYP3A4 催化和抑制的毒理学重要性
基本信息
- 批准号:9275987
- 负责人:
- 金额:$ 34.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-01 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAddressAffectAffinityAgricultureAllosteric RegulationAreaAttenuatedBehaviorBindingBinding SitesBiochemicalCYP3A4 geneCarcinogensCatalysisCessation of lifeChemical StructureChemicalsClinical TrialsComplexConsumptionCrystallizationCytochrome P450DataDevelopmentDietDietary FlavonoidDockingDrug InteractionsDrug toxicityEnvironmental PollutantsEnzymesExhibitsFailureFlavonoidsGoalsHIV InfectionsHealthHepatitis CHerbicidesHumanInsecticidesInvestigationKineticsKnowledgeLeadLigand BindingLightMapsMetabolismModelingMolecular ConformationNADPOccupationsPeripheralPesticidesPharmaceutical PreparationsPharmacologic SubstancePlantsPlayPreventionProcessProgesteroneProtein DynamicsProtein IsoformsPublic HealthQuantitative Structure-Activity RelationshipResearchRitonavirRoentgen RaysRoleSiteStructureSubstrate SpecificitySurfaceTestingTimeToxic effectToxicologyWithdrawalXenobiotic MetabolismXenobioticsanalogbasebiophysical techniquesclinically relevantdesigndrug developmentdrug efficacydrug metabolismenvironmental chemicalin vivoinhibitor/antagonistinsightinter-individual variationnoveloxidationpharmacophorepublic health relevancestoichiometry
项目摘要
DESCRIPTION (provided by applicant): Human cytochrome P450 3A4 (CYP3A4) is the most abundant and clinically relevant xenobiotic-metabolizing P450 in humans and is well known for its extreme promiscuity in substrate specificity and allosteric behavior. In addition to the metabolism of drugs and endogenous compounds, CYP3A4 is implicated in oxidation and bioactivation of pesticides, insecticides, herbicides, carcinogens and environmental pollutants. CYP3A4 can also be inhibited and activated by xenobiotics, which may lead to undesired drug-drug interactions, toxicity and human death. Despite the central role of CYP3A4 in drug metabolism, its mechanism of inhibition and activation are still poorly understood. This proposal is designed to address key issues in both areas of the CYP3A4 research and centers on our advances in the structural and functional investigation of the CYP3A4- ligand binding process. The goal of Aim 1 is to optimize the CYP3A4 inhibitor pharmacophore model that was built based on our studies of analogs of ritonavir, the most potent pharmacoenhancer marketed to date. We will accurately identify the pharmacophoric determinants using novel, rationally designed compounds, which will be further optimized based on structural and functional interpretations. The structure-based CYP3A4-specific inhibitor pharmacophore could assist in identification and early elimination of potential CYP3A4 inactivators during development of drugs and other chemicals used in agriculture and public health, as well as designing more potent pharmacoenhancers. The second part of the proposal focuses on the allosteric behavior of CYP3A4, thought to arise from the multiple substrate binding. CYP3A4 can be activated by various xenobiotics and natural dietary compounds, such as plant flavonoids, but the underlying mechanism is still under debate. Our recent findings suggest that the substrate-access channel rather than the previously identified peripheral area serves as a high affinity effector binding sie. The goal of Aim 2 is to test this hypothesis by comparing the relative importance of the peripheral and intra-channel sites in the CYP3A4 activation by flavonoid-like molecules. Using an integrated structural, biochemical and biophysical approach, we will assess how disruption of these areas affects protein dynamics, substrate binding stoichiometry, kinetics and metabolism. These studies will provide novel insights into the mechanism of CYP3A4 activation, substrate cooperativity and drug-drug interactions, which is essential for prediction/prevention of chemical toxicity and understanding interindividual differences in metabolism of drugs, dietary compounds and environmental chemicals.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Irina F Sevrioukova其他文献
Irina F Sevrioukova的其他文献
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{{ truncateString('Irina F Sevrioukova', 18)}}的其他基金
Toxicological importance of CYP3A4 catalysis and inhibition
CYP3A4 催化和抑制的毒理学重要性
- 批准号:
10358992 - 财政年份:2016
- 资助金额:
$ 34.76万 - 项目类别:
Toxicological importance of CYP3A4 catalysis and inhibition
CYP3A4 催化和抑制的毒理学重要性
- 批准号:
10580711 - 财政年份:2016
- 资助金额:
$ 34.76万 - 项目类别:
STUDIES ON STRUCTURAL HOMOLOGUES, PUTIDAREDOXIN REDUCTASE & APOPTOSIS INDUCING F
腐胺氧还蛋白还原酶结构同系物的研究
- 批准号:
7370370 - 财政年份:2006
- 资助金额:
$ 34.76万 - 项目类别:
STRUCTURAL HOMOLOGUES, PUTIDAREDOXIN REDUCTASE & APOPTOSIS INDUCING FACTOR
结构同系物,腐胺氧还蛋白还原酶
- 批准号:
6976260 - 财政年份:2004
- 资助金额:
$ 34.76万 - 项目类别:
STRUCTURE OF CYTOCHROME P450 REDOX PARTNER COMPLEXES
细胞色素 P450 氧化还原伙伴复合物的结构
- 批准号:
6018443 - 财政年份:1999
- 资助金额:
$ 34.76万 - 项目类别:
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