MECHANISM OF PROMISCUOUS INHIBITION BY SMALL MOLECULE AGGREGATION

小分子聚集的混杂抑制机制

基本信息

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The scientific community has long been troubled by the presence of nonspecific small molecules that inhibit proteins other than their hypothesized targets. The behavior of a large and diverse subset of these inhibitors can be explained by a common mechanism: aggregation. At micromolar concentrations some nonspecific molecules form large aggregates that inhibit a wide range of unrelated soluble proteins. From previous studies we know that inhibition results from the direct interaction of protein and aggregates. This interaction is reversible and does not result in denaturation, but the extent of our understanding stops there. How does binding to the aggregate lead to inhibition? Does the aggregate bind to a particular protein surface or is it nonspecific? Does binding restrain or induce dynamic motion in the protein? I will use deuterium exchange mass spectrometry to address these questions.Since we know that aggregates induce changes subtler than denaturation, it is necessary that we use a more sensitive technique. Mass spectrometry coupled to deuterium exchange of amide hydrogens provides evidence of how exposed certain regions are to solvent. This allows us to examine the accessibility of surface protons and the overall dynamics of the enzyme through the exchange of core (or buried) protons. We predict that aggregates inhibit by altering the normal dynamic motions of the enzyme. Additionally, we will be able to determine whether there is a particular surface to which the aggregate binds. There are few techniques that allow this level of sensitivity and among them mass spectrometry is the most practical. These studies will provide insight into the mechanism of promiscuous inhibition by aggregation, thus elucidating a novel interaction between small molecules and their biological targets.
这个子项目是众多研究子项目之一

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Brian K Shoichet其他文献

Follow your lead
听从你的领导
  • DOI:
    10.1038/nchembio.1484
  • 发表时间:
    2014-03-18
  • 期刊:
  • 影响因子:
    13.700
  • 作者:
    Brian K Shoichet
  • 通讯作者:
    Brian K Shoichet

Brian K Shoichet的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Brian K Shoichet', 18)}}的其他基金

Development and Testing of New Computational Methods for Ligand Discovery and Mechanism
配体发现和机制的新计算方法的开发和测试
  • 批准号:
    10707444
  • 财政年份:
    2017
  • 资助金额:
    $ 0.18万
  • 项目类别:
Development and Testing of New Computational Methods for Ligand Discovery and Mechanism
配体发现和机制的新计算方法的开发和测试
  • 批准号:
    10406014
  • 财政年份:
    2017
  • 资助金额:
    $ 0.18万
  • 项目类别:
Development and Testing of New Computational Methods for Ligand Discovery and Mechanism
配体发现和机制的新计算方法的开发和测试
  • 批准号:
    10170435
  • 财政年份:
    2017
  • 资助金额:
    $ 0.18万
  • 项目类别:
Development and Testing of New Computational Methods for Ligand Discovery and Mechanism
配体发现和机制的新计算方法的开发和测试
  • 批准号:
    9275655
  • 财政年份:
    2017
  • 资助金额:
    $ 0.18万
  • 项目类别:
ANNOTATION OF PROTEIN FUNCTION BY LIGAND DESCRIPTORS
通过配体描述符对蛋白质功能进行注释
  • 批准号:
    8363607
  • 财政年份:
    2011
  • 资助金额:
    $ 0.18万
  • 项目类别:
MECHANISM OF PROMISCUOUS INHIBITION BY SMALL MOLECULE AGGREGATION
小分子聚集的混杂抑制机制
  • 批准号:
    8363768
  • 财政年份:
    2011
  • 资助金额:
    $ 0.18万
  • 项目类别:
A WEB-BASED AUTOMATIC MOLECULAR DOCKING SYSTEM
基于网络的自动分子对接系统
  • 批准号:
    8363598
  • 财政年份:
    2011
  • 资助金额:
    $ 0.18万
  • 项目类别:
DESIGN AND TESTING OF DOCKING ALGORITHMS
对接算法的设计和测试
  • 批准号:
    8363579
  • 财政年份:
    2011
  • 资助金额:
    $ 0.18万
  • 项目类别:
ANNOTATION OF PROTEIN FUNCTION BY LIGAND DESCRIPTORS
通过配体描述符对蛋白质功能进行注释
  • 批准号:
    8170534
  • 财政年份:
    2010
  • 资助金额:
    $ 0.18万
  • 项目类别:
DESIGN AND TESTING OF DOCKING ALGORITHMS
对接算法的设计和测试
  • 批准号:
    8170498
  • 财政年份:
    2010
  • 资助金额:
    $ 0.18万
  • 项目类别:

相似海外基金

Collaborative Research: NSF-DFG: CAS: Electrochemical Hydrogenation of Amides and Esters
合作研究:NSF-DFG:CAS:酰胺和酯的电化学氢化
  • 批准号:
    2140205
  • 财政年份:
    2022
  • 资助金额:
    $ 0.18万
  • 项目类别:
    Standard Grant
Collaborative Research: NSF-DFG: CAS: Electrochemical Hydrogenation of Amides and Esters
合作研究:NSF-DFG:CAS:酰胺和酯的电化学氢化
  • 批准号:
    2140196
  • 财政年份:
    2022
  • 资助金额:
    $ 0.18万
  • 项目类别:
    Standard Grant
Atroposelective Synthesis of Hindered Amides - Exploration of Synthetic Peptide Catalysts -
受阻酰胺的天体选择性合成-合成肽催化剂的探索-
  • 批准号:
    504378162
  • 财政年份:
    2022
  • 资助金额:
    $ 0.18万
  • 项目类别:
    WBP Fellowship
Development of Peptide Chemical Modification Enabled by N-Halogenation of Amides
酰胺 N-卤化实现的肽化学修饰的发展
  • 批准号:
    22H02743
  • 财政年份:
    2022
  • 资助金额:
    $ 0.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Modulating Signaling Endocannabinoids and Fatty Acid Amides
调节信号传导内源性大麻素和脂肪酸酰胺
  • 批准号:
    10532252
  • 财政年份:
    2021
  • 资助金额:
    $ 0.18万
  • 项目类别:
CAREER: SusChEM: Iron Catalysts for the Reduction of Amides
职业:SusChEM:用于还原酰胺的铁催化剂
  • 批准号:
    2146728
  • 财政年份:
    2021
  • 资助金额:
    $ 0.18万
  • 项目类别:
    Continuing Grant
Modulating Signaling Endocannabinoids and Fatty Acid Amides
调节信号传导内源性大麻素和脂肪酸酰胺
  • 批准号:
    10399712
  • 财政年份:
    2021
  • 资助金额:
    $ 0.18万
  • 项目类别:
Nickel-Catalyzed Alpha-Arylation of Secondary Amides
镍催化仲酰胺的α-芳基化
  • 批准号:
    558383-2020
  • 财政年份:
    2020
  • 资助金额:
    $ 0.18万
  • 项目类别:
    Canadian Graduate Scholarships Foreign Study Supplements
Function of primary fatty acid amides as lipid mediators
伯脂肪酸酰胺作为脂质介质的功能
  • 批准号:
    20K21285
  • 财政年份:
    2020
  • 资助金额:
    $ 0.18万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
Catalytic Synthesis of Pharmaceutical Amides in Water
水中催化合成药用酰胺
  • 批准号:
    EP/T01430X/1
  • 财政年份:
    2020
  • 资助金额:
    $ 0.18万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了