Use of Bioinformatics and Genetics to Identify a New Class of Drugs for Neurological Disease

利用生物信息学和遗传学来鉴定一类治疗神经系统疾病的新药物

基本信息

批准号：
10196360
负责人：
SCOTT James MYERS
金额：
$ 42.53万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196360
关键词：
Alzheimer&apos s Disease Binding Binding Sites Bioinformatics Biological Markers Cations Cell physiology Cells Central Nervous System Diseases Clinical Codon Nucleotides Cognition Complex Disease Progression Drug Industry Genetic Genetic Variation Glutamate Receptor Glutamates Glycine Health Human Impaired cognition In Vitro Industry Intellectual functioning disability Investigation Learning Legal patent Libraries Ligands Literature Long-Term Potentiation Mediating Memory Memory impairment Methods Modification Mutagenesis Mutation N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neurologic Neurons Patients Pharmaceutical Chemistry Pharmaceutical Preparations Play Population Probability Process Property Quality of life Role Series Site Structure Synapses Synaptic Transmission Synaptic plasticity System Testing Therapeutic Intervention Variant analog base clinical development cognitive ability design detector developmental disease experimental study family burden genetic analysis ifenprodil improved in vivo inhibitor/antagonist innovation insight lead optimization mutant nervous system disorder novel novel drug class novel therapeutics patch clamp positive allosteric modulator pressure programs protein structure receptor receptor function scaffold screening small molecule virtual

项目摘要

NMDA receptors (NMDARs) can trigger synaptic plasticity due to their ability to act as coincident detectors of simultaneous neuronal firing and excitatory synaptic input, which can strengthen synapses by a cellular process known as long term potentiation (LTP). NMDARs play a critical role in cognition and memory formation, which is compromised in several neurological diseases. NMDARs are assemblies of two GluN1 subunits and two GluN2A-D subunits. Increased expression of GluN2B-containing NMDARs in vivo can enhance synaptic plasticity and memory, suggesting that GluN2B-selective positive allosteric modulators may facilitate learning. Finding ways to improve synaptic plasticity and memory formation could improve quality of life for patients with Alzheimer’s disease or intellectual disability. GluN2B-selective negative allosteric modulators (i.e. inhibitors) such as ifenprodil and analogues bind to the GluN1/GluN2B heterodimer amino terminal domain (ATD) interface. However, no drug-like GluN2B- selective positive allosteric modulator (i.e. potentiator) that binds to this site has been discovered despite the pharmaceutical industry screening many millions of compounds. Thus, if such modulators exist, they are absent from large screening libraries, which provide the starting point for virtually all medicinal chemistry efforts. In this proposal we exploit two advances in our understanding of NMDARs that could enable us to find new scaffolds for positive modulators. First, a crystallographic study of GluN2B-selective NMDAR inhibitors demonstrated a unique binding mode for the 93-series of Emory compounds, which occupy three branches of the triangular pocket located at the interface between the GluN1 and GluN2B ATDs. No other GluN2B- selective modulator binds in this fashion. We also discovered two GluN1 mutations near the modulator binding site that convert the action of Emory-synthesized GluN2B inhibitors, but not other classes of GluN2B inhibitors, into potentiators. This is the first evidence that a GluN2B-selective potentiator of NMDARs acting at the ifenprodil site can exist, and provides insight into what that molecule does to protein structure to make it a potentiator. We believe this insight together with structure-based design methods will support discovery of GluN2B potentiators of wild type NMDARs. Second, genetic variation in the healthy population has revealed that GluN1 and GluN2B residues in contact with ifenprodil have significantly fewer variants than expected, revealing that the ifenprodil binding pocket is under selective pressure. The only possible reasons for this are that these residues are critically important for receptor function, or an undiscovered endogenous modulator binds within this pocket and is important for health. We propose to test these two possibilities, including a screen of CSF for actions of a small molecule that binds within this pocket. We will carry out two sets of experiments: (1) design and synthesize GluN2B-selective positive allosteric modulators that act at the ifenprodil site, and (2) screen CSF for an endogenous modulator acting at the ifenprodil binding site.

NMDA 受体 (NMDAR) 可以触发突触可塑性，因为它们能够充当同步探测器同时神经元放电和兴奋性突触输入，可以通过细胞增强突触称为长时程增强 (LTP) 的过程在认知和记忆中发挥着关键作用。 NMDAR 的形成在多种神经系统疾病中受到损害，它是两个 GluN1 的组装体。亚基和两个 GluN2A-D 亚基体内含有 GluN2B 的 NMDAR 表达增加。增强突触可塑性和记忆力，表明 GluN2B 选择性正变构调节剂可能促进学习。寻找提高突触可塑性和记忆形成的方法可以提高学习质量。阿尔茨海默病或智力障碍患者的生活。 GluN2B 选择性负变构调节剂（即抑制剂），例如艾芬地尔和类似物，与 GluN1/GluN2B 异二聚体氨基末端结构域 (ATD) 界面然而，没有类似药物的 GluN2B-。尽管发现了与该位点结合的选择性正变构调节剂（即增效剂）制药行业筛选了数百万种化合物，因此，如果存在此类调节剂，它们就是。大型筛选库中不存在，而大型筛选库为几乎所有药物化学提供了起点在本提案中，我们利用了对 NMDAR 理解的两项努力进展，使我们能够找到首先，GluN2B 选择性 NMDAR 抑制剂的晶体学研究。展示了 Emory 93 系列化合物的独特结合模式，该化合物占据三个分支位于 GluN1 和 GluN2B ATD 之间界面的三角形口袋的形状无其他 GluN2B-。我们还在调节剂结合附近发现了两个 GluN1 突变。转换 Emory 合成的 GluN2B 抑制剂的作用位点，但不转换其他类别的 GluN2B 这是第一个证据表明 NMDAR 的 GluN2B 选择性增强剂起作用。艾芬地尔位点上可以存在，并提供深入了解该分子对蛋白质结构的作用，从而使我们相信这种洞察力与基于结构的设计方法将支持发现。其次，健康人群中的遗传变异已被揭示。与艾芬地尔接触的 GluN1 和 GluN2B 残基的变异明显少于预期，表明艾芬地尔结合袋处于选择性压力下，唯一可能的原因是。这些残基对于受体功能至关重要，或者是一种未被发现的内源性调节剂结合在这个口袋里，对健康很重要，我们建议测试这两种可能性，包括一个。我们将进行两组脑脊液筛选，以了解结合在该口袋内的小分子的作用。实验：（1）设计并合成GluN2B选择性正变构调节剂，作用于 ifenprodil 位点，(2) 筛选 CSF 中作用于 ifenprodil 结合位点的内源性调节剂。