Investigating Ionotropic Glutamate Receptor Interfaces as Novel Drug Targets.

研究离子型谷氨酸受体界面作为新药物靶点。

• 批准号: MR/M000435/1
• 负责人: Philip Biggin
• 金额: $ 46.84万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM000435%2F1
• 关键词: Investigating; Ionotropic; Glutamate; Receptor; Interfaces

A key goal of modern medicine is to develop better therapeutic approaches for the treatment of diseases and conditions associated with the brain. This is one of the most challenging goals of medicinal science, hampered in part by the complexity of the brain itself. Another major stumbling block is the problem of developing new drugs that do not have severe side-effects, an issue often cited as one of the reasons why patients stop taking their prescriptions. The transmission of nerve signals in the body and brain is dependent on proteins called receptors. Most of this neurotransmission that governs memory and learning is controlled by ionotropic glutamate receptors, so-called, because upon binding of glutamate (the neurotransmitter) they open a pore that passes through the membrane of the neuron and allows positively charged ions (sodium and potassium) to pass through it. This is the basis of nerve signals in the brain. It is therefore perhaps unsurprising that glutamate receptors have been implicated in many neurological conditions of the central nervous system (CNS) ranging from epilepsy to Alzheimer's disease. There are many different subtypes of glutamate receptors and it appears that certain subtypes of these receptors are implicated to different extents in different neurological conditions. Therefore, to avoid unwanted side-effects, drugs that act at these receptors should be as specific as possible. The problem is that they all bind the same neurotransmitter, glutamate, and therefore this is actually quite difficult. The differences between the subtypes manifest themselves away from the glutamate-binding site, and is apparent in terms of some of the properties the receptors exhibit. For example, how quickly they open or how long it takes for them to close, can be controlled by regions of the receptor away from the binding site. These regions are sometime referred to as allosteric sites and because they have not been subjected to the same evolutionary pressure as the main (orthosteric) binding site offer a potential route to greater specificity. In other words, our chances of obtaining greater specificity with compounds at these sites should be much greater than at the glutamate-binding site.In our previous work, we were able to show how, for one particular sub-family of receptors called kainate receptors, a region away from the glutamate-binding site could control the dynamic properties of the receptor. In particular, this region contains separate binding sites for sodium and chloride ions. In this proposal we'd like to not only explore this aspect further, but also to investigate the possibility that new drugs with fewer side-effects can be targeted to this region. By targeting in this way, we are hopeful that we can develop new improved therapies for the treatment of epilepsy and neuropathic pain. Our proposal utilizes the power of molecular simulations to provide atomic-level detail of what controls the way this binding site behaves. A full understanding of this is necessary if we are to have any chance of developing compounds that act in a predictable way. The results we will generate will be verified and tested by our collaborators in McGill University in Canada.

现代医学的一个关键目标是开发更好的治疗方法来治疗与大脑相关的疾病和病症。这是医学科学最具挑战性的目标之一，部分原因是大脑本身的复杂性。另一个主要的障碍是开发没有严重副作用的新药的问题，这个问题经常被认为是病人停止服用处方药的原因之一。神经信号在身体和大脑中的传输依赖于称为受体的蛋白质。大多数控制记忆和学习的神经传递是由离子型谷氨酸受体控制的，因为谷氨酸（神经递质）结合后，它们打开一个穿过神经元膜的孔，允许带正电荷的离子（钠和钾）通过，这是大脑神经信号的基础。因此，谷氨酸受体与从癫痫到阿尔茨海默病的中枢神经系统（CNS）的许多神经学病症有关可能并不令人惊讶。谷氨酸受体有许多不同的亚型，并且似乎这些受体的某些亚型在不同的神经系统疾病中有不同程度的牵连。因此，为了避免不必要的副作用，作用于这些受体的药物应尽可能具有特异性。问题是它们都与同样的神经递质谷氨酸结合，因此这实际上很困难。亚型之间的差异表现在远离谷氨酸结合位点，并且在受体表现出的一些特性方面是明显的。例如，它们打开的速度或关闭所需的时间可以由受体远离结合位点的区域控制。这些区域有时被称为变构位点，并且因为它们没有受到与主要（正构）结合位点相同的进化压力，所以提供了更大特异性的潜在途径。换句话说，我们在这些位点上获得更高特异性的机会应该比在谷氨酸结合位点上获得更高的特异性。在我们以前的工作中，我们能够证明，对于一种称为红藻氨酸受体的特殊受体亚家族，远离谷氨酸结合位点的区域可以控制受体的动态特性。特别是，该区域包含钠离子和氯离子的单独结合位点。在这个提议中，我们不仅想进一步探索这方面，而且还想研究副作用更少的新药可以针对这一地区的可能性。通过以这种方式靶向，我们希望我们可以开发新的改进疗法来治疗癫痫和神经性疼痛。我们的建议利用分子模拟的力量来提供控制这种结合位点行为方式的原子级细节。如果我们想有机会开发出以可预测的方式发挥作用的化合物，就必须充分了解这一点。我们将产生的结果将由我们在加拿大麦吉尔大学的合作者进行验证和测试。

项目成果

Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes.

• DOI: 10.1016/j.neuron.2016.01.038
• 发表时间: 2016-03-16
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Dawe GB;Musgaard M;Aurousseau MRP;Nayeem N;Green T;Biggin PC;Bowie D
• 通讯作者: Bowie D

Functional Validation of Heteromeric Kainate Receptor Models.

异聚红藻氨酸受体模型的功能验证。

• DOI: 10.1016/j.bpj.2017.08.047
• 发表时间: 2017
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Paramo T