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CRCNS: Computational and experimental study of dopamine and serotonin transporter

CRCNS：多巴胺和血清素转运蛋白的计算和实验研究

基本信息

批准号：
8477163
负责人：
JEFFRY D. MADURA
金额：
$ 26.82万
依托单位：
DUQUESNE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8477163
关键词：
Antidepressive Agents Anxiety Disorders Applications Grants Area Attention Binding Binding Sites Cell membrane Cocaine Collaborations Computational Technique Crystallization Development Docking Dopamine Generations Goals Hyperactive behavior Instruction Leucine Location Madura Mental Depression Methylphenidate Modeling Molecular Molecular Conformation Molecular Models Mutagenesis Narcolepsy Nature Parkinson Disease Process Publishing Quantitative Structure-Activity Relationship Research Scientist Structure Substance Addiction Substance abuse problem Techniques Testing Therapeutic Transmembrane Domain base chronic pain comparative computer studies design dopamine transporter inhibitor/antagonist model development molecular dynamics molecular modeling monoamine nervous system disorder neurotransmitter transport novel psychostimulant research study serotonin transporter three-dimensional modeling

项目摘要

This CRCNS grant application proposes structure, function, and dynamic studies on the plasma membrane dopamine (DAT) and serotonin transporters (SERT). Recently, the arduous process of identifying DAT and SERT substrate and inhibitor binding sites received an unexpected boost with the crystallization of the homologous LeuTAa leucine transporter. This crystal structure revealed hinged regions of transmembranes (TMs) 1 and 6 adjacent to the leucine substrate, with TMs 3, 8 and 10 also delineating the binding pocket. Through comparative molecular modeling techniques we have published a three-dimensional model of DAT using LeuTAa. The modeling also suggests novel inhibitor binding sites, nonidentical to dopamine, that can be tested via molecular pharmacological techniques. This project brings together a unique team of computational scientists, medicinal chemists, and pharmacologists to examine the structure, function, and dynamics of monoamine neurotransporters (MATs). The overall goal of this project is to determine binding locations for psychostimulant and antidepressant inhibitors of neurotransmitter transport, and the conformational states involved in the transport mechanism. State-of-the-art computational techniques in areas of docking, advanced molecular dynamics simulations, QSAR and structure-based design will be used to identify important residues and regions of the transporter to perform mutagenesis experiments as well as direct the synthesis of novel compounds that inhibit binding of non-neurotransmitter molecules yet retain transporter activity. In summary, this proposal (1) includes collaborations between computational and/or modeling experts (Madura research group), experimental neuropharmacoiogists (Surratt research group) and medicinal chemists (Lapinsky research group); (2) involves intense, dynamic interactions among these research groups in the model development and refinement of neurotransporters; and (3) leads to the development and testing of new models that provide a framework for the design of experiments and the generation of new hypotheses to reveal mechanisms underlying normal nervous system disease states.

这项CRCNS拨款申请提出了质膜多巴胺（DAT）和血清素转运体（SERT）的结构、功能和动态研究。最近，随着同源LeuTAa亮氨酸转运体的结晶，鉴定DAT和SERT底物和抑制剂结合位点的艰巨过程得到了意想不到的推动。该晶体结构揭示了与亮氨酸底物相邻的跨膜（TMs） 1和6的铰接区域，TMs 3、8和10也描绘了结合袋。通过比较分子建模技术，我们利用LeuTAa发表了DAT的三维模型。该模型还提出了新的抑制剂结合位点，与多巴胺不同，可以通过分子药理学技术进行测试。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

LeuT conformational sampling utilizing accelerated molecular dynamics and principal component analysis.

利用加速分子动力学和主成分分析进行 LeuT 构象采样。

DOI：
10.1016/j.bpj.2012.05.002
发表时间：
2012
期刊：
Biophysical journal
影响因子：
3.4
作者：
Thomas,JamesR;Gedeon,PatrickC;Grant,BarryJ;Madura,JeffryD
通讯作者：
Madura,JeffryD

Polyglutamine Solution-State Structural Propensity Is Repeat Length Dependent.

聚谷氨酰胺溶液状态结构倾向依赖于重复长度。

DOI：
10.1021/acs.jpcb.9b01433
发表时间：
2019
期刊：
The journal of physical chemistry. B
影响因子：
0
作者：
Jakubek,RyanS;Workman,RileyJ;White,StephenE;Asher,SanfordA
通讯作者：
Asher,SanfordA

Identification of a novel selective serotonin reuptake inhibitor by coupling monoamine transporter-based virtual screening and rational molecular hybridization.

DOI：
10.1021/cn200044x
发表时间：
2011-06-08
期刊：
ACS CHEMICAL NEUROSCIENCE
影响因子：
5
作者：
Nolan, Tammy L.;Lapinsky, David J.;Talbot, Jeffery N.;Indarte, Martin;Liu, Yi;Manepalli, Sankar;Geffert, Laura M.;Amos, Mary Ellen;Taylor, Phillip N.;Madura, Jeffry D.;Surratt, Christopher K.
通讯作者：
Surratt, Christopher K.

Molecular dynamics of leucine and dopamine transporter proteins in a model cell membrane lipid bilayer.