Predicting Rates and Regioselectivity in Cytochrome P450 Mediated Reactions

预测细胞色素 P450 介导反应的速率和区域选择性

基本信息

  • 批准号:
    8008956
  • 负责人:
  • 金额:
    $ 10万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-01-28 至 2010-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by Applicant): Summary and Abstract- The main goals of this proposal are 1) to provide the fundamental knowledge required for understanding Cytochrome P450 mediated reaction mechanism with regards to rates, regioselectivity, and binding, and 2) to provide computational tools for predicting the metabolic component of ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity). These are highly significant goals that will positively impact almost all drug development projects and decrease the time required to develop new therapeutics. These goals will be described in terms of the following four Specific Aims: Aim 1) At present the number of active-oxygen species used by Cytochrome P450 remains controversial, and we propose that this may explain why predictive methods for metabolism are limited to around 85% accuracy. Predictive models for metabolism are important in drug design, and have the potential to save lives by decreasing the time it takes to develop new drugs. Aim 2) Specific Aim 2 explores binding afforded to substrates designed to coordinate to the iron of the heme (type II binding) providing specificity for P450 enzymes by increasing affinity up to 250-fold. This is significant because systemic administration of drugs meant to inhibit a single P450 enzyme normally leads to broad inhibition of a number of P450 enzymes, upsetting homeostasis, and causing drug-drug interactions. Aim 3) Computational prediction of P450 mediated rates remains one of the most important targets of researchers working in the field. Specific Aim 3 will establish the features important in such predictions. If this goal can be met we can understand the important features involved in predicting the clearance of a drug from the body, and we move closer to the goal of virtual drug design. Aim 4) With the ever-expanding number of computational methods and research publications in predictive ADMET, Specific Aim 4 will provide common sets of publicly accessible test set databases along with open-source predictive code allowing different computational ADMET methods to be tested against common benchmarks. This is particularly important since the majority of the methods are developed in-house and the test sets are not published. We hypothesize that by publishing open source code to a public web site for metabolic predictions that we can translate the results of ours' and others' research into the public domain resulting in a significant increase in the use and quality of these tools. We also hypothesize that having a common set of data available to all researchers will encourage validation, comparison, and enhancement of ADMET models. Public Health Relevance: Narrative- The purpose of this grant application is to understand the important features of cytochrome P450 enzymes with respect to drug metabolism, and drug design. Cytochrome P450 enzymes are the most important drug metabolizing enzymes and are responsible for most drug metabolism. While the majority of the reactions mediated by this enzymes family are benign, a number cause activation to reactive species that can cause cancer and toxicity. Furthermore, many life threatening drug-drug interactions occur from drugs slowing cytochrome P450 mediated reactions. This grant application will develop methods to design new drugs faster, and safer than we can presently through an increased understanding of the rates and binding affinities or P450 mediated reactions.
描述(由申请人提供):摘要和摘要-本提案的主要目标是 1) 提供了解细胞色素 P450 介导的反应机制所需的基础知识,包括速率、区域选择性和结合,以及 2) 提供用于预测 ADMET 代谢成分(吸收、分布、代谢、排泄、毒性)的计算工具。这些都是非常重要的目标,将对几乎所有药物开发项目产生积极影响,并减少开发新疗法所需的时间。这些目标将根据以下四个具体目标进行描述: 目标 1) 目前,细胞色素 P450 使用的活性氧种类的数量仍然存在争议,我们认为这可以解释为什么代谢预测方法的准确度仅限于 85% 左右。代谢预测模型在药物设计中非常重要,并且有可能通过减少开发新药所需的时间来拯救生命。目标 2) 特异性目标 2 探索与底物的结合,该底物设计用于与血红素的铁配位(II 型结合),通过将亲和力提高至 250 倍,提供 P450 酶的特异性。这一点很重要,因为全身性施用旨在抑制单一 P450 酶的药物通常会导致多种 P450 酶的广泛抑制,扰乱体内平衡,并引起药物间相互作用。目标 3) P450 介导速率的计算预测仍然是该领域研究人员最重要的目标之一。具体目标 3 将建立此类预测中重要的特征。如果能够实现这一目标,我们就可以了解预测药物从体内清除所涉及的重要特征,并且我们离虚拟药物设计的目标更近了。目标 4) 随着预测 ADMET 中计算方法和研究出版物数量的不断增加,Specific Aim 4 将提供可公开访问的测试集数据库的通用集以及开源预测代码,允许根据通用基准测试不同的计算 ADMET 方法。这一点尤其重要,因为大多数方法都是内部开发的,并且测试集尚未发布。我们假设,通过将开源代码发布到公共网站进行代谢预测,我们可以将我们和其他人的研究结果转化为公共领域,从而显着提高这些工具的使用和质量。我们还假设,为所有研究人员提供一组通用数据将鼓励 ADMET 模型的验证、比较和增强。 公共健康相关性:叙述 - 本拨款申请的目的是了解细胞色素 P450 酶在药物代谢和药物设计方面的重要特征。细胞色素P450酶是最重要的药物代谢酶,负责大多数药物代谢。虽然该酶家族介导的大多数反应是良性的,但许多反应会导致活性物质的激活,从而导致癌症和毒性。此外,许多危及生命的药物相互作用是由于药物减缓细胞色素 P450 介导的反应而发生的。这项拨款申请将通过加深对 P450 介导反应的速率和结合亲和力或 P450 介导的反应的了解,开发比我们目前更快、更安全地设计新药的方法。

项目成果

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Jeffrey P Jones其他文献

Jeffrey P Jones的其他文献

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{{ truncateString('Jeffrey P Jones', 18)}}的其他基金

Improving prediction of drug interactions mediated by time-dependent inhibitors
改进对时间依赖性抑制剂介导的药物相互作用的预测
  • 批准号:
    9199095
  • 财政年份:
    2016
  • 资助金额:
    $ 10万
  • 项目类别:
Understanding the Metabolic Impact of Aldehyde Oxidase on New Drug Design
了解醛氧化酶对新药设计的代谢影响
  • 批准号:
    8471732
  • 财政年份:
    2012
  • 资助金额:
    $ 10万
  • 项目类别:
Understanding the Metabolic Impact of Aldehyde Oxidase on New Drug Design
了解醛氧化酶对新药设计的代谢影响
  • 批准号:
    8643264
  • 财政年份:
    2012
  • 资助金额:
    $ 10万
  • 项目类别:
Understanding the Metabolic Impact of Aldehyde Oxidase on New Drug Design
了解醛氧化酶对新药设计的代谢影响
  • 批准号:
    8829301
  • 财政年份:
    2012
  • 资助金额:
    $ 10万
  • 项目类别:
Understanding the Metabolic Impact of Aldehyde Oxidase on New Drug Design
了解醛氧化酶对新药设计的代谢影响
  • 批准号:
    8266119
  • 财政年份:
    2012
  • 资助金额:
    $ 10万
  • 项目类别:
Covalent Binding Methods for Early Drug Development
早期药物开发的共价结合方法
  • 批准号:
    6650434
  • 财政年份:
    2003
  • 资助金额:
    $ 10万
  • 项目类别:
TRIPLE QUADRUPOLE MASS SPECTROMETER
三重四极杆质谱仪
  • 批准号:
    6291666
  • 财政年份:
    2001
  • 资助金额:
    $ 10万
  • 项目类别:
CYTOCHROME P450 MODELS FOR RISK ASSESSMENT
用于风险评估的 CYTOCHROME P450 模型
  • 批准号:
    6382241
  • 财政年份:
    1998
  • 资助金额:
    $ 10万
  • 项目类别:
Predicting Rates and Regioselectivity in Cytochrome P450 Mediated Reactions
预测细胞色素 P450 介导反应的速率和区域选择性
  • 批准号:
    8102775
  • 财政年份:
    1998
  • 资助金额:
    $ 10万
  • 项目类别:
Predicting Rates and Regioselectivity in Cytochrome P450 Mediated Reactions
预测细胞色素 P450 介导反应的速率和区域选择性
  • 批准号:
    7876607
  • 财政年份:
    1998
  • 资助金额:
    $ 10万
  • 项目类别:

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