MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES
阿片肽的分子动力学构象
基本信息
- 批准号:6106788
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Summary of Work: Molecular modeling comprised
of molecular dynamics, conformational searching and
superimpositions with crystal structures were used to propose a
delta-opioid antagonist pharmacophore based on two sources: (1)
the constrained and weakly bioactive cyclo(Dmt-Tic) and (2) the
crystalline structure of N,N-dimethyl-Dmt-Tic-OH. In fact, the
model of H-Dmt-Tic-OH and cyclo(Dmt-Tic) overlapped with the
coordinates of the crystalline peptide with 0.6 and 03 rms,
respectively; rms values under 1.0 indicate very close correlation in
conformation. Characteristics of the 3-D structure are a cis peptide
bond, gauche+ orientation of the Tic side chain, a near parallel
orientat and close proximity of the aromatic rings. In fact, the ring
distance of 5.4 angstroms appears to a common feacture of
delta-opioid antagonists and differs from the more extended
distances of aromatic rings (11-12 angstroms) found for delta and
mu agonists. Based on the physicochemical data and further 2D 1H
NMR involving temperature and solvent variation with di-, tri- and
heptapeptide analogues will confirm these observations in spite of
the inherent flexibility of the longer peptides. The data readily
confirm the notion that peptide conformation exists in solution and
is a required feature for recognition with high affinity by opioid
receptor sites. New opioid di- and pentapeptide antagonists were
developed based on the proposed pharmacophore for a delta-opioid
agonist; for example, Dmt-D-Phe di- and pentapeptide analogues
revealed that these compounds were mu-receptor antagonists.
Molecualr modeling studies are continuing to delineate the
differences between delta and mu antagonists and how their
structure is compatible with that of the proposed receptor binding
sites. Furthermore, with the availability of many more small peptide
analogues with dual receptor binding characteristics or selective for
the mu opioid receptor will assis in using molecular modeling in a
predictive mode. The data will be used to develop delta- and
mu-opioid antagonist pharmacophore which will serve as a scaffold
for further design of highly potent ligands. The availability of
mu-opioid antagonists would be compatible in drug treatment
against cocain, heroine and morphine addiction.
工作总结:分子建模包括
分子动力学,构象搜索,
叠加与晶体结构被用来提出一个
基于两个来源的δ-阿片拮抗剂药效团:(1)
受约束的和弱生物活性的环(Dmt-Tic)和(2)
N,N-二甲基-Dmt-Tic-OH的晶体结构。实际上
H-Dmt-Tic-OH和cyclo(Dmt-Tic)模型与
结晶肽的坐标为0.6和03 rms,
均方根值低于1.0表明与
构象三维结构的特征是顺式肽
键,左+Tic侧链的取向,近平行
芳环的取向和紧密接近。事实上,戒指
5.4埃的距离似乎是一个共同的特征,
δ-阿片类拮抗剂,并不同于更广泛的
δ和δ的芳环距离(11-12埃)
mu激动剂。基于物理化学数据和进一步的2D 1H
涉及温度和溶剂变化的NMR,
七肽类似物将证实这些观察结果,
较长肽的固有柔性。数据很容易
证实了肽构象存在于溶液中的概念,
是阿片样物质以高亲和力识别所需特征
受体位点。新的阿片样物质二肽和五肽拮抗剂,
基于δ-阿片样物质的拟议药效团开发
激动剂;例如,Dmt-D-Phe二肽和五肽类似物
表明这些化合物是μ-受体拮抗剂。
分子模拟研究正在继续描绘
δ和μ拮抗剂之间的差异以及它们如何
结构与所提出的受体结合的结构相容
网站.此外,随着更多小肽的可用性,
具有双重受体结合特征或对
μ阿片受体将阿西斯分子模拟在一个
预测模式这些数据将用于开发德尔塔-和
μ-阿片拮抗剂药效团,其将用作支架
用于进一步设计高效配体。的可用性
μ-阿片拮抗剂在药物治疗中是相容的
对抗可卡因海洛因和吗啡成瘾
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 }}
LAWRENCE H LAZARUS其他文献
LAWRENCE H LAZARUS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('LAWRENCE H LAZARUS', 18)}}的其他基金
相似海外基金
Towards more complete models and improved computer simulation tools for Liquid Composite Molding (LCM)
为液体复合成型 (LCM) 打造更完整的模型和改进的计算机模拟工具
- 批准号:
RGPIN-2022-04495 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Discovery Grants Program - Individual
Computer simulation of yeast metabolism by data-driven ensemble modeling
通过数据驱动的集成建模对酵母代谢进行计算机模拟
- 批准号:
22H01879 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (B)
Computer simulation studies of crystallization in structured ternary fluids
结构三元流体结晶的计算机模拟研究
- 批准号:
2717178 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Studentship
Computer simulation of confined polymers and 2D catenated-ring networks
受限聚合物和二维链环网络的计算机模拟
- 批准号:
RGPIN-2022-03086 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Discovery Grants Program - Individual
A computer simulation study to unveil fluid behavior of the beam-on target of a fusion neutron source
揭示聚变中子源射束目标流体行为的计算机模拟研究
- 批准号:
22K03579 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Aggregation process of amyloid-beta peptides on a membrane on a lipid membrane studied by computer simulation
计算机模拟研究淀粉样β肽在脂膜上的聚集过程
- 批准号:
21K06040 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving cardiac valve implant outcomes with advanced computer simulation
通过先进的计算机模拟改善心脏瓣膜植入效果
- 批准号:
nhmrc : 2002892 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Ideas Grants
Computer simulation of cell polarization and migration in 3D
3D 细胞极化和迁移的计算机模拟
- 批准号:
563522-2021 - 财政年份:2021
- 资助金额:
-- - 项目类别:
University Undergraduate Student Research Awards
Computer Simulation of a Semiflexible Polymer Confined to a Dual-Nanocavity Geometry
限制在双纳米腔几何结构中的半柔性聚合物的计算机模拟
- 批准号:
563544-2021 - 财政年份:2021
- 资助金额:
-- - 项目类别:
University Undergraduate Student Research Awards
Diversity Research Supplement for Combining Experiments and Computer Simulation to Improve the Stem Cell Differentiation Process
结合实验和计算机模拟改善干细胞分化过程的多样性研究补充
- 批准号:
10550022 - 财政年份:2021
- 资助金额:
-- - 项目类别: