Rational discovery of new DOR chemotypes to prevent addiction and overdose

合理发现新的 DOR 化学型以防止成瘾和过量

基本信息

  • 批准号:
    9033099
  • 负责人:
  • 金额:
    $ 20.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-04-01 至 2017-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Opioid analgesics are the most efficient tool in pain management; however, high tolerance and addiction liabilities also make them the most abused class of medication, resulting in millions of cases of drug overdose and more than 15,000 deaths in the US each year. Specific modulation of d-opioid receptor (DOR) represents one of the most promising strategies to control tolerance and addiction to opioid drugs; however, only a few chemotypes of DOR-selective compounds have been explored. A new unique opportunity to expand the repertoire of DOR compounds by discovery of novel chemotypes with desirable functional profiles is enabled by structural characterization of opioid receptors, including new high resolution structures of DOR/naltrindole complex at 1.8 Å, and DOR with bifunctional peptide DIPP-NH2. The structures reveal atomic details of ligand binding and provide a reliable 3D framework for rational discovery of new ligands targeting orthosteric or allosteric pockets of DOR. The project will primarily focus on two therapeutically beneficial profiles: (a) bifunctional MOR agonists/DOR antagonists known to reduce tolerance and side effects of opioid therapy, and (b) allosteric ligands that modulate DOR activity only in the presence of endogenous opioid. In the exploratory R21 phase of the project we will perform large scale structure-based virtual ligand screening of more than 6 million available compounds to select small sets of candidate hits, and then experimentally test and identify new bifunctional and allosteric ligands. The most promising chemical scaffolds, and validated structural models will be employed then in an iterative lead optimization at the R33 phase. Both initial screening and lead optimization phases will employ state-of-the-art structure-based approaches which have proven to be highly effective in recent applications to GPCRs. Success of the program will result in new insights into drug action, lead to new DOR ligands with desired properties, and establish a solid platform for rational structure-based discovery of safer and less addictive opioid therapies.


项目成果

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VSEVOLOD KATRITCH其他文献

VSEVOLOD KATRITCH的其他文献

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{{ truncateString('VSEVOLOD KATRITCH', 18)}}的其他基金

Efficient synthon-based modular screening of Giga-to-Terra-scale virtual libraries
基于合成子的高效模块化筛选千兆级到太级虚拟文库
  • 批准号:
    10504984
  • 财政年份:
    2022
  • 资助金额:
    $ 20.42万
  • 项目类别:
Efficient synthon-based modular screening of Giga-to-Terra-scale virtual libraries
基于合成子的高效模块化筛选千兆级到太级虚拟文库
  • 批准号:
    10710170
  • 财政年份:
    2022
  • 资助金额:
    $ 20.42万
  • 项目类别:
Structure Function of CB1 Cannabinoid Receptor
CB1大麻素受体的结构功能
  • 批准号:
    10001488
  • 财政年份:
    2016
  • 资助金额:
    $ 20.42万
  • 项目类别:
Rational Anthrax Vaccine with Structural Epitopes on VLP
VLP 上具有结构表位的合理炭疽疫苗
  • 批准号:
    6555409
  • 财政年份:
    2002
  • 资助金额:
    $ 20.42万
  • 项目类别:

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