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：
8274837
负责人：
JEFFRY D. MADURA
金额：
$ 28.8万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8274837
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.

此CRCN授予应用程序提出了有关质膜多巴胺（DAT）和5-羟色胺转运蛋白（SERT）的结构，功能和动态研究。最近，鉴定DAT和SERT底物和抑制剂结合位点的艰巨过程通过同源Leutaa Leucine转运蛋白的结晶而产生了意外的提升。这种晶体结构揭示了与亮氨酸基板相邻的跨膜（TMS）1和6的铰链区域，TMS 3、8和10也描绘了结合口袋。通过比较分子建模技术，我们发布了使用Leutaa的DAT的三维模型。该建模还表明，可以通过分子药理技术对多巴胺非相同的新型抑制剂结合位点进行测试。该项目汇集了一个独特的计算科学家，药物学家和药理学家团队，以检查单胺神经递送蛋白（MATS）的结构，功能和动力学。该项目的总体目标是确定神经递质转运的精神刺激剂和抗抑郁剂抑制剂的结合位置，以及涉及运输机制的构象状态。最先进的计算技术在对接，高级分子动力学模拟，QSAR和基于结构的设计领域的最先进的计算技术将用于识别转运蛋白的重要残基和区域以执行诱变实验，并直接合成抑制结合结合的新型化合物非神经递质分子但保持转运蛋白活性。总而言之，该提案（1）包括计算和/或建模专家（Madura Research Group），实验性神经药物学家（Surratt Research Group）和药物化学家（Lapinsky Research Group）之间的合作；（2）涉及这些研究小组之间在模型开发和改进神经逆转录蛋白中的激烈，动态的相互作用；（3）导致开发和测试新模型，这些模型为实验设计和产生的新假设提供了一个框架，以揭示正常神经系统疾病状态的基础机制。